Shunt for redistributing atrial blood volume

ABSTRACT

A shunt for regulating blood pressure between a patient&#39;s left atrium and right atrium comprises an anchor comprising a neck region, first and second end regions, and a conduit affixed with the anchor that formed of a biocompatible material that is resistant to transmural and translation tissue ingrowth and that reduces a risk of paradoxical embolism.

FIELD OF THE INVENTION

This application generally relates to percutaneously placed implants andmethods for redistributing blood from one cardiac chamber to another toaddress pathologies such as heart failure (HF), myocardial infarction(MI) and pulmonary arterial hypertension (PAH).

BACKGROUND OF THE INVENTION

Heart failure is the physiological state in which cardiac output isinsufficient to meet the needs of the body or to do so only at a higherfiling pressure. There are many underlying causes of HF, includingmyocardial infarction, coronary artery disease, valvular disease,hypertension, and myocarditis. Chronic heart failure is associated withneurohormonal activation and alterations in autonomic control. Althoughthese compensatory neurohormonal mechanisms provide valuable support forthe heart under normal physiological circumstances, they also play afundamental role in the development and subsequent progression of HF.

For example, one of the body's main compensatory mechanisms for reducedblood flow in HF is to increase the amount of salt and water retained bythe kidneys. Retaining salt and water, instead of excreting it viaurine, increases the volume of blood in the bloodstream and helps tomaintain blood pressure. However, the larger volumes of blood also causethe heart muscle, particularly the ventricles, to become enlarged. Asthe heart chambers become enlarged, the wall thickness decreases and theheart's contractions weaken, causing a downward spiral in cardiacfunction. Another compensatory mechanism is vasoconstriction of thearterial system, which raises the blood pressure to help maintainadequate perfusion, thus increasing the load that the heart must pumpagainst.

In low ejection fraction (EF) heart failure, high pressures in the heartresult from the body's attempt to maintain the high pressures needed foradequate peripheral perfusion. However, as the heart weakens as a resultof such high pressures, the disorder becomes exacerbated. Pressure inthe left atrium may exceed 25 mmHg, at which stage, fluids from theblood flowing through the pulmonary circulatory system transudate orflow out of the pulmonary capillaries into the pulmonary interstitialspaces and into the alveoli, causing lung congestion and if untreatedthe syndrome of acute pulmonary edema and death.

Table 1 lists typical ranges of right atrial pressure (RAP), rightventricular pressure (RVP), left atrial pressure (LAP), left ventricularpressure (LVP), cardiac output (CO), and stroke volume (SV) for a normalheart and for a heart suffering from HF. In a normal heart beating ataround 70 beats/minute, the stroke volume needed to maintain normalcardiac output is about 60 to 100 milliliters. When the preload,after-load, and contractility of the heart are normal, the pressuresrequired to achieve normal cardiac output are listed in Table 1. In aheart suffering from HF, the hemodynamic parameters change (as shown inTable 1) to maintain peripheral perfusion.

TABLE 1 Parameter Normal Range HF Range RAP (mmHg) 2-6   6-20 RVSP(mmHg) 15-25  20-80 LAP (mmHg) 6-12 15-50 LVEDP (mmHg) 6-12 15-50 CO(liters/minute) 4-8  2-6 SV (milliliters/beat) 60-100 30-80

HF is generally classified as either systolic heart failure (SHF) ordiastolic heart failure (DHF). In SHF, the pumping action of the heartis reduced or weakened. A common clinical measurement is the ejectionfraction, which is a function of the blood ejected out of the leftventricle (stroke volume) divided by the maximum volume in the leftventricle at the end of diastole or relaxation phase. A normal ejectionfraction is greater than 50%. Systolic heart failure generally causes adecreased ejection fraction of less than 40%. Such patients have heartfailure with reduced ejection fraction (HFrEF). A patient with HFrEF mayusually have a larger left ventricle because of a phenomenon called“cardiac remodeling” that occurs secondarily to the higher ventricularpressures.

In DHF, the heart generally contracts normally, with a normal ejectionfraction, but is stiffer, or less compliant, than a healthy heart wouldbe when relaxing and filling with blood. Such patients are said to haveheart failure with preserved ejection fraction (HFpEF). This stiffnessmay impede blood from filling the heart and produce backup into thelungs, which may result in pulmonary venous hypertension and lung edema.HFpEF is more common in patients older than 75 years, especially inwomen with high blood pressure.

Both variants of HF have been treated using pharmacological approaches,which typically involve the use of vasodilators for reducing theworkload of the heart by reducing systemic vascular resistance, as wellas diuretics, which inhibit fluid accumulation and edema formation, andreduce cardiac filling pressure. No pharmacological therapies have beenshown to improve morbidity or mortality in HFpEF whereas several classesof drugs have made an important impact on the management of patientswith HFrEF, including renin-angiotensin antagonists, beta blockers, andmineralocorticoid antagonists. Nonetheless, in general, HF remains aprogressive disease and most patients have deteriorating cardiacfunction and symptoms over time. In the U.S., there are over 1 millionhospitalizations annually for acutely worsening HF and mortality ishigher than for most forms of cancer.

In more severe cases of HFrEF, assist devices such as mechanical pumpsare used to reduce the load on the heart by performing all or part ofthe pumping function normally done by the heart. Chronic leftventricular assist devices (LVAD), and cardiac transplantation, oftenare used as measures of last resort. However, such assist devicestypically are intended to improve the pumping capacity of the heart, toincrease cardiac output to levels compatible with normal life, and tosustain the patient until a donor heart for transplantation becomesavailable. Such mechanical devices enable propulsion of significantvolumes of blood (liters/min), but are limited by a need for a powersupply, relatively large pumps, and pose a risk of hemolysis, thrombusformation, and infection. Temporary assist devices, intra-aorticballoons, and pacing devices have also been used.

Various devices have been developed using stents to modify bloodpressure and flow within a given vessel, or between chambers of theheart. For example, U.S. Pat. No. 6,120,534 to Ruiz is directed to anendoluminal stent for regulating the flow of fluids through a bodyvessel or organ, for example, for regulating blood flow through thepulmonary artery to treat congenital heart defects. The stent mayinclude an expandable mesh having lobed or conical portions joined by aconstricted region, which limits flow through the stent. The mesh maycomprise longitudinal struts connected by transverse sinusoidal orserpentine connecting members. Ruiz is silent on the treatment of HF orthe reduction of left atrial pressure.

U.S. Pat. No. 6,468,303 to Amplatz et al. describes a collapsiblemedical device and associated method for shunting selected organs andvessels. Amplatz describes that the device may be suitable to shunt aseptal defect of a patient's heart, for example, by creating a shunt inthe atrial septum of a neonate with hypoplastic left heart syndrome(HLHS). That patent also describes that increasing mixing of pulmonaryand systemic venous blood improves oxygen saturation, and that the shuntmay later be closed with an occluding device. Amplatz is silent on thetreatment of HF or the reduction of left atrial pressure, as well as onmeans for regulating the rate of blood flow through the device.

Implantable interatrial shunt devices have been successfully used inpatients with severe symptomatic heart failure. By diverting or shuntingblood from the left atrium (LA) to the right atrium (RA), the pressurein the left atrium is lowered or prevented from elevating as high as itwould otherwise (left atrial decompression). Such an accomplishmentwould be expected to prevent, relieve, or limit the symptoms, signs, andsyndromes associated of pulmonary congestion. These include severeshortness of breath, pulmonary edema, hypoxia, the need for acutehospitalization, mechanical ventilation, and death.

Shunt flow is generally governed by the pressure gradient between theatria and the fluid mechanical properties of the shunt device. Thelatter are typically affected by the shunt's geometry and materialcomposition. For example, the general flow properties of similar shuntdesigns have been shown to be related to the mean interatrial pressuregradient and the effective orifice diameter.

Percutaneous implantation of interatrial shunts generally requirestransseptal catheterization immediately preceding shunt deviceinsertion. The transseptal catheterization system is placed from anentrance site in the femoral vein, across the interatrial septum in theregion of fossa ovalis (FO), which is the central and thinnest region ofthe interatrial septum. The FO in adults is typically 15-20 mm in itsmajor axis dimension and ≤3 mm in thickness, but in certaincircumstances may be up to 10 mm thick. LA chamber access may beachieved using a host of different techniques familiar to those skilledin the art, including but not limited to: needle puncture, styletpuncture, screw needle puncture, and radiofrequency ablation. Thepassageway between the two atria is dilated to facilitate passage of ashunt device having a desired orifice size. Dilation generally isaccomplished by advancing a tapered sheath/dilator catheter system orinflation of an angioplasty type balloon across the FO. This is the samegeneral location where a congenital secundum atrial septal defect (ASD)would be located.

U.S. Patent Publication No. 2005/0165344 to Dobak, III describesapparatus for treating heart failure that includes a tubular conduithaving a emboli filter or valve, the device configured to be positionedin an opening in the atrial septum of the heart to allow flow from theleft atrium into the right atrium. Dobak discloses that shunting ofblood may reduce left atrial pressures, thereby preventing pulmonaryedema and progressive left ventricular dysfunction, and reducing LVEDP.Dobak describes that the device may include deployable retention struts,such as metallic arms that exert a slight force on the atrial septum onboth sides and pinch or clamp the device to the septum.

Two types of percutaneously implantable shunts have been described inthe medical and patent literature. In short-term, small-size clinicaltrials, both types have been shown to be associated with improvements insymptoms, quality of life measurements, and exercise capacity. Bothshunts also have observed and theoretical drawbacks, which may limittheir effectiveness and use.

The first type of shunt is henceforth referred to as an orifice-platemesh shunt. Orifice-plate mesh shunts comprise a metallic mesh thatwraps around both sides of the septum with a hole in the center andanatomically mimics the location and geometrical characteristics of asmall congenital secundum ASD. The shunt geometry generally resembles athin plate with a hole in it. In most embodiments, the “plate” comprisesboth mesh material and atrial septal tissue encased by the mesh. Oneexample of such devices, designed by Corvia Medical, Inc., TewksburyMass., consists of a self-expanding nitinol mesh that forms a pair ofdisc-like flanges with an open orifice in the center. The maximaldiameter of the discs is 19.4 mm and the orifice diameter is 8 mm. Eachdisc flange has multiple truss-like legs that deploy into a presetconfiguration that wraps around the LA and RA sides of the interatrialseptum and applies a clamping force to the tissue.

Another example of such a mesh type device, developed by OcclutechInternational AB, Helsingborg, Sweden, resembles a dual-disc occluderused for closing congenital secundum ASDs, which additionally includes ashort open barrel orifice in the center that connects the two discs.

A major benefit of the foregoing orifice-plate mesh shunts over othershunt designs is simplicity of manufacture. Although relatively simplein theory and construction, orifice-plate mesh type shunts have severalimportant drawbacks that are expected to reduce their overall potentialfor clinical safety and effectiveness.

A first drawback of orifice-plate devices is the susceptibility tonarrow or close during the post-implantation healing period. Forexample, neoendocardial tissue ingrowth, referred to as pannus, growsfrom the underlining tissue to cover the mesh and narrow or partiallyocclude the shunt orifice. During the period following implantation,local trauma caused by crossing and dilating the FO, plus the chroniceffects of continuous pressure applied by the mesh material on theseptal tissue, provoke a localized healing response. This responseentails activation of an inflammatory process, attracting lymphocytesand macrophages to the area of tissue injury. These inflammatory cellsin turn release a variety of cytokines that signal fibroblasts andsmooth-muscle cells from the wound margins to dedifferentiate, migrate,proliferate and encapsulate affected portions of the implanted device.The fibroblasts and smooth muscle cells then secrete extracellularmatrix material composed of collagen and proteoglycans, whichextracellular matrix forms the bulk of the pannus. The duration of thishealing phase in humans is typically up to 6-9 months, but may be longerif there is a chronic source for tissue injury such as devicecompression or erosion of adjacent tissue. Eventually this pannus iscovered with neoendothelial cells, causing the pannus growth to stop orstabilize. In the long term, the collagen of the pannus remodels, butgenerally retains its space occupying properties. Such tissue ingrowthtypically spreads over the surfaces of the implant's struts, mesh, ordiscs, and may substantially narrow the orifice lumen or even entirelyocclude the shunt. Narrowing or occlusion of the shunt prevents LAdecompression and limits any positive effect for the patient.

The degree of luminal narrowing may be quite variable between patientsdue to differences in the severity of local injury—the more injury, themore exaggerated the pannus formation. Also, variability results fromdifferences in host wound healing responses. For example, the amount andcharacter of extracellular matrix may affect the duration of healing andamount of material deposited. Thus, for an orifice-plate mesh shunt, theeventual orifice lumen size will be highly variable. These processeswill be familiar to one skill in the art as it is generally analogous tothe type of late lumen loss that occurs in arteries when bare metalstents are used to treat atherosclerotic stenosis.

In a trial described in the publication, “A Transcatheter IntracardiacShunt Device for Heart Failure with Preserved Ejection Fraction (REDUCELAP-HF): A Multicentre, Open-label, Single-arm, Phase 1 Trial” byHasenfuss, et al., 14 of 64 patients implanted with an orifice-platemesh shunt device had no demonstrable flow across the shunt ontransthoracic echocardiographic Doppler imaging at 6 months afterimplantation. It has not reported whether the shunts were occluded or ifthe imaging study was simply too technically difficult to tell forcertain. Although additional interventional cardiology procedures may beundertaken to restore lost luminal patency, such procedures may poseunacceptable risks, including death and stroke from embolization of theorifice-clogging material.

A second drawback of an orifice-plate mesh shunt is the potential forparadoxical embolization. Paradoxical embolization refers tothromboembolism originating in the venous vasculature (venousthromboembolism or VTE), such that an embolus traverses right-to-leftthrough a cardiac shunt into the systemic arterial circulation. The mostsevere complication of paradoxical embolization occurs when an emboluslodges in the cerebral circulation with resulting cerebral infarction(stroke). Similarly, if a paradoxical embolus enters the coronaryarterial circulation, myocardial infarction (MI) may ensue. Otherembolic syndromes result from embolization to the mesenteric, renal, andperipheral arteries supplying the limbs. These may cause respectively,ischemic bowel syndrome, hematuria with worsening renal function, andgangrene requiring amputation.

Most frequently, VTE in adults is the consequence of in situ thrombosisin the deep veins (deep venous thrombosis or DVT) of the lowerextremities or pelvis. For the most part, clinically relevant venousemboli develop in the popliteal veins or more proximally in larger veinsof the upper thigh or pelvis. In patients with DVT involving thepopliteal vein, the venous diameter averaged 11.4 mm (range from 6.2 mmto 20.1 mm). Often, emboli are described as having the form of a cast ofthe vein's lumen with a width equal to the diameter of the vein oforigin. These thrombi also tend to be elongated, corresponding to thelength of the occluded venous segment.

The risk factors associated with thromboembolic disease include avariety of anatomic, physiological, rheological variables and diseasestates. Heart failure is a well-recognized risk factor for DVT and VTE,especially in patients with reduced left ventricular systolic function.About 3% of deaths in heart failure patients are due to VTE, usuallyassociated with pulmonary embolism. Patients with transvenousendocardial pacing leads and an intracardiac shunt have a 3-foldincreased risk of systemic thromboembolism, suggesting that paradoxicalembolism is a contributing underlying cause. There is evidence that therisk of paradoxical embolism is directly related to the orifice size ofnaturally occurring atrial level shunts such as ASD and patent foramenovale (PFO). The presence of an atrial septal aneurysm is an additionalrisk factor. For example, as described in the publication “TranscatheterAmplatzer Device Closure of Atrial Septal Defect and Patent ForamenOvale in Patients with Presumed Paradoxical Embolism” by Khositsth, etal., in a series of 103 adult patients with paradoxical embolization, anASD was present in 12%, whereas PFO was present in 81%. In patients withclinically significant ASD referred for closure, the incidence ofparadoxical embolus has been reported to be up to 14%.

It has been asserted that in order for VTE to enter the systemiccirculation, the prevailing LA to RA pressure gradient must betemporarily reduced, eliminated or reversed so that blood will eitherflow slowly across the shunt, cease to flow across the shunt or flowretrograde across the shunt. Echo/Doppler imaging studies often revealsome amount of shunting in both directions (bi-directional shunting) inpatients with congenital ASD, even when LA to RA flow predominates.Bidirectional shunting may be best demonstrated when a subject performsa Valsalva maneuver (straining caused by exhalation against a closedglottis). Valsalva increases intrathoracic pressure, which causes the RAand LA pressures to equalize after several seconds and then for the RApressure to transiently exceed LA pressure on exhalation. Intermittentbidirectional flow also may be observed at rest when the interatrialpressure gradient is low, or intermittently during the cardiac cyclewhen LA contraction is delayed compared to RA contraction (interatrialconduction delay). This is seen especially when the atria are enlargedor diseased, such as in heart failure. In this setting, interatrialelectrical conduction delay results in retardation of LA contraction.Bidirectional shunting can also be seen transiently during inspiration,when venous return to the RA is increased, during coughing, withabdominal compression, during forced exhalation, or in the presence ofsevere tricuspid valve regurgitation. Chronically increased pulmonaryarterial pressure, as seen in severe pulmonary hypertension, whetherprimary or secondary to chronic lung disease, recurrent pulmonaryembolism, or due to chronic right ventricular volume overload, has beenassociated with chronic and more severe RA to LA shunting.

Additional phenomena associated with RA to LA shunting are diminishedpulmonary blood flow and decreased arterial oxygen saturation due tosystemic venous admixing. When these findings are also transient, theyare generally well tolerated. Thus, prevention of significant or largerparadoxical emboli is the primary concern rather than preventing reverseshunting per se. As the consequences of paradoxical embolization can becatastrophic, it is desirable particularly in high-risk patients, thatan implantable shunt be equipped with mechanism(s) that limit orminimize the chances of paradoxical embolization or minimize the chancesof transporting large emboli.

From these data, it seems reasonable to expect that an orifice-platemesh shunt, by virtue of its anatomic similarities with congenitalsecundum ASD, would have a similar risk of paradoxical embolization. Itis easily understandable that a thin plate-orifice mesh type ofartificial shunt might be more susceptible to paradoxical embolizationthan other types of shunts with longer orifice geometries, e.g., anozzle. For any given quanta of RA volume (blood or thrombus), thestatistical likelihood of traversing retrograde across the shunt andinto the LA would be expected to be a complex function of the durationof pressure gradient reversal, flow patterns in the RA, shunt tunneldistance affecting the length of the flow velocity streamlines, and flowvelocity and orifice or lumen size.

A third drawback of an orifice-plate mesh shunt is that percutaneousremoval from the shunt body is only possible at the time ofimplantation. Should the shunt become a nidus for infection, developfatigue or corrosion fractures of its metallic framework, or erode orotherwise impinge on other vital cardiac structures, it cannot beremoved by percutaneous retrieval/removal techniques. This is becausethe shunt, with its large “footprint” on the interatrial septum, isencased in pannus tissue. Attempts at percutaneous removal may result intearing of the septum, pericardial tamponade, and device embolizationinto the systemic circulation, resulting in death or the need foremergency surgery. Safe removal would require performing open heartsurgery. This entails that the heart be bypassed using an extracorporealmembrane pump oxygenator (cardiopulmonary bypass), so the heart can beopened, the shunt removed, and the septum repaired. Performing suchsurgical procedures in patients with already established severe heartfailure, including its frequently associated co-morbid conditions suchas peripheral, cerebrovascular, and coronary artery disease, renaldysfunction, and diabetes, would be expected to have substantial risksfor mortality or severe morbidity.

A fourth drawback of an orifice-plate mesh type of shunt is that itsgeometry renders it relatively inefficient in supporting high flow. Forany given pressure gradient across the shunt, the geometry of an orificeplate requires a larger orifice because it has a reduced effectiveorifice size compared with other geometries, such as a venturi-shapedlumen, or a conical shaped nozzle. This is because with an office-plate,there are more energy losses associated with eddy currents at the edgesof the plate. Orifice-plate geometries may be categorized as having arelatively low discharge coefficient, which is a dimensionlessfluid-mechanical parameter that relates flow to actual orifice size. Forpractical purposes, the discharge coefficient is the ratio of areas ofthe exiting jet vena contracta, which is the narrowest portion of thejet, compared to the shunt orifice. For example, the coefficient ofdischarge for orifice plates placed in pipes tends to be approximately0.6, but rarely exceeds 0.65. The discharge coefficient is affected bythe orifice and chamber dimensions, the pressure gradient, and theviscosity of blood and/or the Reynolds number of the specific flowcondition. This differs from the more efficient passage of flow througha classic venturi type of narrowing, where the discharge coefficientusually exceeds 0.9 and is typically in the range of 0.94 to 0.98. Theresult is that, in comparison with more efficient shunt lumengeometries, an orifice-plate mesh shunt requires a larger orificediameter to accommodate the same amount of flow for any given pressuredifferential across the shunt.

A fifth drawback of an orifice-plate mesh shunt is that it occupies alarge area or footprint on the interatrial septum. The flanges of thedevice that anchor the shunt typically occupy the entire area of thefossa ovalis and may overlap adjoining muscular portions of theinteratrial septum. These flanges exert persistent pressure on theseptum, causing injuring and stimulating an exaggerated healing responseas described above. Also, the rigidity of the mesh may interfere withthe normal motion of the muscular septum. The flanges additionally mayimpinge on adjacent cardiac structures such as the roof of the leftatrium, the ostia of the pulmonary veins, and the aorta root and sinusesof Valsalva, where due to chronic rubbing contact or sandwichingcompressive forces, they may erode into these vital structures. Sucherosion has been associated with severe complications including cardiactamponade and death. For example, the similarly sized Amplatzer ASD discocclusion device described above has been occasionally associated witherosion into adjoining tissues with resulting catastrophic outcomes.

Additional issues associated with placing relatively large devices withcomplex three-dimensional geometries are potential difficulties inpositioning the shunts accurately in the FO, obtaining sufficient tissueanchoring to prevent migration, and having devices conform toirregularities of the cardiac anatomy. For example, in a report ofattempted implantation of orifice-plate mesh shunts in 66 patients inthe above cited publication authored by Hasenfuss, et al., deviceplacement was not possible in two patients. And of the 64 implantedpatients, the device had to be removed and re-implanted in another 3patients due to misplacement, migration, or embolization of the firstattempted implant.

Finally, the large footprint on the atrial septum may hinder or renderimpossible performing other interventional procedures that requiretransseptal access. The large flange diameter and small mesh pore sizesgenerally make catheter crossing of the atrial septum possible onlythrough the central shunt orifice itself. Transseptal procedures usingsmall diameter catheters, such as atrial fibrillation RF ablation, maybe conducted through the orifice-plate lumen only if it is notobstructed by pannus and the orifice location permits entry into allfour pulmonary veins. Other structural heart disease procedures thathave large diameter delivery systems and/or require crossing the FO inspecific locations may encounter difficulties or simply not be possible.These procedures include left atrial appendage occlusion, mitral valveedge-to-edge (“MitraClip”) repair, and transvascular mitral valvereplacement. For example, placing of a MitraClip optimally requirescrossing the FO in its superior-posterior quadrant. The guiding catheterhas a tip inner diameter of 7.7 mm (23 Fr). Similar transseptal accessis needed to perform reconstructive mitral annuloplasty with theCardioband device marketed by Valtech. In these cases, the onlyalternatives might be higher risk therapeutic approaches involvingtrans-left ventricular apical access or open heart surgery.

The second type of shunt is referred to as a valved unidirectionalshunt. These shunts attempt to overcome some of the drawbacks oforifice-plate devices. For example, valved unidirectional shunts haveembodiments containing a one-way or check-valve to limit reverseshunting and paradoxical embolization. Some of the valve configurationsare designed to open when the LA-RA pressure gradient exceeds apredefined threshold. Other valve configurations close only when the RApressure exceeds LA pressure (reversed gradient).

U.S. Pat. No. 9,034,034 to Nitzan, the entire contents of which areincorporated by reference herein, solves many of the drawbacks ofplate-like orifice mesh shunts describe above. An embodiment of theNitzan-type shunt comprises an hourglass or diabolo outer shape, havinga small FO footprint minimizing septal injury, which is expected tominimize pannus growth and obliteration of the shunt lumen. Its one-wayvalve also is designed to reduce the potential for reverse shunting andparadoxical embolization. The relatively small footprint of the shunt incontact with the septum and encapsulated collapsible nitinol frame isdesigned to facilitate percutaneous extraction from the septum andretrieval from the body using a standard goose-neck snare and large-boresheath, thus making the device more easily retrieved. The venturitube-like inner lumen of the diabolo shape provides better bulk flowcharacteristics, permitting a smaller orifice for the same amount offlow compared to orifice plate shunts. And finally, the small footprinton the FO and the hourglass shape are designed to facilitate accurateplacement and retention during implantation. This geometry alsominimizes interference with normal motion of the interatrial septum, andthe small footprint provides space surrounding the shunt for otherpotential interventional procedures that require transseptalcatheterization.

One embodiment of the Nitzan design, manufactured by V-Wave, Ltd(Caesarea, Israel), designed to support unidirectional left-to-rightflow, comprises a self-expanding frame constructed from a laser-cutnitinol tube. The frame includes five sinusoidal circumferential strutsinterconnected by six longitudinal bars. The frame is heat-set so thatit has an asymmetrical hourglass shape or a diabolo shape. The shunt isdeployed so that the neck (5.3 mm outer diameter) is placed across theFO and secured in place by its external surface geometry. The shunt'swidest portion has a conical shape with an approximately 14.3 mm outerdiameter at the LA end of the shunt, which serves as an “entry” port onthe distal end of the entry funnel. The entry funnel is deployed in theleft atrium, and registers the neck of the shunt to the region of theFO. A second, slightly narrower bell-shaped portion forms the exitportion of the shunt, which expands to a maximum outer diameter of 11.4mm at the RA end of the shunt. The shunt does not require flanges,discs, or tissue anchors to secure it in place. Septal retention isachieved without applying persistent pressure, tension or rubbingcontact on the tissue adjoining the device neck.

The V-Wave shunt has a single inner lumen where flow is entrained intothe entry funnel in the LA and passes through the constricted neckhaving a 5.1 mm inner diameter, which resembles a venturi-type orifice,and then exits through a bioprosthetic valve positioned near the RA endof the shunt. The entry funnel and the central neck region areencapsulated with expanded polytetrafluoroethylene (“ePTFE”) to form askirt or cover over the frame. The skirt is designed to facilitatelaminar flow and limit pannus ingrowth during device healing. The exitbell-shaped portion contains three, glutaraldehyde-fixed, porcinepericardial leaflets sutured to the frame at the right atrial extent ofthe ePTFE encapsulation. The leaflets are designed to create a smoothexit channel and remain in the open position, closing only when the RApressure exceeds LA pressure by 1-2 mmHg, thus preventing reverseright-to-left shunting.

For deployment, the V-Wave shunt is compressed in a loading tube whereit is attached to a triple-latch cable delivery catheter. The loadingtube is inserted into a 14F delivery sheath that has been previouslyplaced after a transseptal catheterization from the right femoral veinacross the FO. The shunt then is advanced through the sheath until theentry funnel has been deployed in the LA. The entire system is withdrawnas a unit until the LA funnel is in contact with the left side of theFO. The delivery catheter latches are unhooked from the shunt, thedelivery catheter withdrawn so the right atrial side of the shunt isheld only by its radial force against the delivery sheath. Then thedelivery sheath is withdrawn, thereby deploying the exit bell-shapedportion of the shunt on the RA side of the FO. Device placement may beguided and confirmed by fluoroscopy and echocardiography, e.g.,intracardiac echo or transesophageal echo.

Pre-clinical testing on the V-Wave shunt was performed in an establishedjuvenile ovine (sheep) model that created an ischemic cardiomyopathyform of heart failure. The sheep were pre-treated with sequentialcoronary artery microembolization as described in the publication,“Chronic Heart Failure Induced by Multiple Sequential CoronaryMicroembolization in Sheep” by Schmitto et al. After several weeks, thesheep manifested evidence of severe left ventricular systolicdysfunction and develop elevated LV, LA, and pulmonary artery pressures.In a 12-week survival study, this V-Wave shunt was associated withsignificant improvements in LA pressure and left ventricular ejectionfraction. All manifestations of worsening heart failure were improvedand in some cases reversed with interatrial shunting. Concurrent controlanimals with established heart failure, but were not implanted with theV-Wave shunt, demonstrated progressive worsening of LV ejectionfraction, and intracardiac/pulmonary pressure during 3-month follow-up.The physiological improvements in shunted animals were substantial eventhough the shunt volume was assessed to be small. The pulmonary bloodflow/systemic blood flow ratio (Qp/Qs) was between 1.1 to 1.2, asmeasured by oximetry, which is consistent with a very small shunt.Naturally occurring ASDs, with a Qp/Qs less than 1.5, are generally leftuntreated as they are well tolerated for decades by the compliant rightheart and pulmonary vasculature, without evidence of worsening rightventricular failure despite mild chronic volume overload. This wasconfirmed in the sheep model where RA and pulmonary artery pressuresdecreased to baseline levels with shunting, but progressively worsenedin the control animals.

A total of 38 patients were implanted with the V-Wave hourglass-shapedshunt having valve leaflets in two similar feasibility studies. Thebaseline characteristics of the combined study populations aresummarized in Table 1 below.

TABLE 1 Baseline characteristics of 38 patients implanted with valvedhourglass-shaped shunt device Age, years 66 ± 9  Male gender, % 92 Bodymass index, kg/m2 30 ± 6  NYHA class, median III (97%), IV (3%) IschemicCardiomyopathy, % 76 DM/HTN/AFIB, % 68/84/53 ACEi-ARB/BB/MRA/DIUR, %78/100/75/94 CRT-D or ICD/CRT-D or CRT-P, % 74/39 NT-proBNP, pg/ml 2640± 2301 eGFR, mL•min−1•1.73 m−2 54 ± 20 6MWT, m 282 ± 114 PCWP, mmHg 20 ±6  RAP, mmHg 8 ± 4 PAP mean, mmHg 30 ± 7  CI, L•min−1•m−2 2.1 ± 0.5 PVR,mmHg/L•min−1 2.9 ± 1.4 LVEF (HFrEF, n = 30), % 26 ± 7  LVEF (HFpEF, n =8), % 50 ± 9  NYHA = New York Heart Association heart failureclassification; DM = diabetes mellitus; HTN = hypertension; AFIB =atrial fibrillation; ACEi-ARB = receiving angiotensin converting enzymeinhibitor or angiotensin receptor blocker; BB = receiving beta blocker;MRA = receiving mineralocorticoid antagonist; DIUR = receiving loopdiuretic; CRT-D = implanted with combination cardiac resynchronizationtherapy pacemaker with ICD; ICD = implantablecardioverter/defibrillator; CRT-P = implanted with cardiacresynchronization therapy pacemaker without combination ICD; NT-proBNP =N-terminal pro b-type natriuretic peptide; eGFR = estimated glomerularfiltration rate; 6MWT/minute walk test distance; PCWP = pulmonarycapillary wedge pressure; RAP = right atrial pressure; PAP = pulmonaryartery pressure; CI = cardiac index; PVR = pulmonary vascularresistance; LVEF = left ventricular ejection fraction; HFrEF = heartfailure with reduced ejection fraction; HFpEF = heart failure withpreserved ejection fraction.These parameters and abbreviations are well known to one skilled in theart.

All patients had New York Heart Association (NYHA) Class III orambulatory Class IV heart failure symptoms at the time of studyenrollment. Patients with either reduced or preserved left ventricularejection fraction were included. There was a high frequency ofco-morbidities known to be associated with a poorer prognosis includingcoronary artery disease, diabetes mellitus, atrial fibrillation, andchronic kidney dysfunction. All patients received appropriateguideline-driven medical and device therapies prior to study enrollment.Patients had evidence of elevated levels of natriuretic peptides,reduced exercise capacity, elevated intra-cardiac and pulmonary arterypressures, increased pulmonary vascular resistance, and reduced cardiacoutput. These factors have also been associated with poor outcomes.Patients were excluded if they had severe right ventricular dysfunctionor severe pulmonary hypertension.

Implantation of the V-Wave shunt was successful in all 38 patients andno device replacements were performed. Shunts remained implanted in theatrial septum without dislodgements, migrations or apparent interferencewith normal septal motion on fluoroscopic or echocardiographic imaging.No shunts have required removal or replacement for infection or strutfracture. Follow-up imaging studies show that there are adjacentlocations on the FO, that are available and amenable for performingtransseptal procedures to treat other cardiac conditions, including, forexample, atrial fibrillation ablation, left atrial appendage occlusion,and mitral valve repair. The valve apparatus, when functioning normally,has been shown to effectively prevent reverse (right-to-left) shunting.Echocardiographic contrast and Doppler studies during rest or Valsalvamaneuver show that there is no reverse shunting in the early monthsafter human implantation. Furthermore, no thromboembolic clinicalevents, including paradoxical embolization, have been observed duringthe first year of follow-up.

Shunt patency is defined as LA to RA flow through the shunt as observedduring transesophageal echo/Doppler study. At 3-months afterimplantation of the V-Wave shunts, patency was confirmed in allpatients. The pulmonary to systemic flow ratio (Qp/Qs), as measured byechocardiography, increased from 1.04±0.22 at baseline to 1.18±0.16shortly after implantation (p<0.03). In the subgroup of 30 patients withHFrEF presented by Dr. William Abraham, MD at TCT 2016 in WashingtonD.C., there were statistically significant (p<0.05) improvements inclinician-assessed symptoms, patient assessed quality-of-life scores,and exercise capacity as measured by a 6-minute hall walk testing at 3,6, and 12 months following implantation There was no deterioration innatriuretic hormone levels, echocardiographic, or hemodynamicparameters. Most importantly, the annualized (Poisson) heart failurehospitalization rate with shunting (0.17 heart failure hospitalizationper patient year), was substantially reduced in comparison to a wellmatched historical control groups (CHAMPION trial Control and Treatmentgroups, 0.90 and 0.67 heart failure hospitalization per patient year,respectively). These data provide adequate proof-of-concept thatinteratrial shunting is of benefit to patients with severe symptomaticheart failure. Moreover, these data strongly support moving forward withlarger-scale clinical trials including randomized clinical trials.

Notwithstanding the initial success observed in the foregoing trial,device occlusion, e.g., shunts having undetectable LA to RA flow, wasobserved in some valved interatrial shunt devices after long-termimplantation, e.g., by 1 year. Further, shunts may develop bidirectionalshunting that was not present early on. Bidirectional shunting isindicative of an incompetent valve, e.g., a valve where one or moreleaflets do not fully coapt during closure, resulting in an open channelfor reversed flow, and depending on the severity of the incompetence,may create a potential path for paradoxical embolus to traverse from theRA to LA.

To assess the effective orifice size of valved shunts over time,transesophageal echo/Doppler measurements of the diameter of the venacontracta, measured on the left-to-right flow jets through the shunt,were found to be consistent with progressive shunt narrowing. The venacontracta diameter monotonically decreased with time after implantationfrom 4.0±1.1 mm just after implantation, to 3.6±1.0 mm at 3 months, and2.7±1.4 mm at 6-12 months (p<0.01). This equates, on average, to shuntslosing more than half of their orifice area by 12 months. Moreover, someof the left-to-right jets appeared to be exiting the shunt at an anglesubstantially different from the long axis of the shunt body. Thisskewing of the jet is consistent with material inside the shunt such asa valve leaflet with impaired mobility, which diverts the direction ofthe jet. This observation gives rise to concern about a decrease in theclinical effectiveness of the shunts over time

Clinical effectiveness also may be measured by the rate ofhospitalization for worsening heart failure. In the 38 patients, duringthe first 6 months after implantation of the V-Wave shunt, thehospitalization rate was 0.16 per patient year, which increased to 0.40per patient year between months 6-12. These data suggest there may be aloss of shunting benefit consistent with the time course associated withshunt narrowing or occlusion.

There are several possible mechanisms working alone or in combinationthat could explain these observations.

The least likely cause of shunt occlusion is collapse of the shunt dueto external forces applied by the septum. For example, it is possiblethat contraction of pannus tissue formed during the later stages ofhealing (remodeling) could result in extrinsic compression of the shunt.However, there is no evidence to support this scenario based on multipleobservations of frame geometry seen during pre-clinical studies andduring follow-up transesophageal echocardiography (TEE), CT, orfluoroscopic imaging in humans. In all cases, the observed shunt framehas not been observed to be extrinsically compressed or in any other waynarrowed, deformed, or fractured.

Another possible mechanism is in situ thrombosis of the shunt. However,all patients were treated with monitored anticoagulation for the firstthree months, or indefinitely if there were other indications forchronic anticoagulation, which was most commonly required in patientswith a history of atrial fibrillation. Subjects were also treatedsimultaneously with low-dose aspirin, which was continued indefinitely.Having experience with prosthetic cardiac valves as a predicate, valvethrombosis would have been expected to be seen earlier, typically within30-45 days after implantation, especially in patients with a history ofsubtherapeutic anticoagulation therapy.

In the 38 patients implanted with the V-Wave valved hourglass-shapedshunt described above, no thrombi were detected on 121 consecutivepost-implantation echocardiograms. These studies systematically lookedfor intracardiac or device thrombus by an independent EchocardiographicCore Laboratory at time points including one day after implantation, andat 1, 3, 6, and 12 months after implantation. None of the patientspresented with stroke or other clinical manifestations of thromboembolicevents. Of 9 patients with suspected shunt occlusion or incompetentvalves, most were taking therapeutic doses of anticoagulants (warfarinor New Oral Anticoagulant agents) at the time the shunt anomaly wasdiscovered. Another reason that thrombosis is unlikely is theobservation of progressive vena contracta narrowing over a time courseof 6 months or more. Thrombosis would be expected to result in suddenlumen loss, and not progress slowly over a period of months.

A third potential cause of occlusion is neoendocardial tissue overgrowthor pannus formation that narrows the lumen at the neck of thehourglass-shaped shunt. Applicants' earlier ovine studies suggestotherwise. Specifically, the shunt lumen surface at the neck of thehourglass contained only microscopic amounts of cellular material. Ongross pathological examination, there was no visible loss of the lumenarea in neck region. A human shunt specimen has been examined in anexplanted heart from a patient that underwent cardiac transplantation2.5 years after shunt implantation. The ePTFE surfaces of the shuntincluding the lumen at the neck contained no pannus formation ornarrowing of any kind.

In another example, a left atrial pressure sensor implanted across theFO by transseptal catheterization and used for guiding the medicaltherapeutic dosing in symptomatic patients with severe heart failure wasobserved to experience pannus formation. In the original embodiment ofthe sensor, the sensing diaphragm, located at the distal end of thesensor module body, protruded into the left atrium by 1-mm beyond itsthree anchoring legs that rested on the left atrial side of the septum.In a later, improved geometry version, the legs were placed moreproximal on the sensor module body so that sensing diaphragm protrudedinto the LA by an additional 1.5 mm.

In a comparative inter-species pathology study, neoendocardial tissue(pannus) formation was observed over the sensing diaphragm in 20 of 31original sensors compared with only 3 of 40 specimens with the improvedgeometry sensor. Of the 20 original sensors with tissue coverage, 7 haddemonstrable artifacts in the LA pressure waveform. In each case withartifacts, pannus formation over the sensing diaphragm had athickness >0.3 mm. These data indicate that when tissue coverage exceedsthis thickness, the tissue interferes with fluid pressure measurement.None of the improved sensors had waveform artifacts or tissuethickness >0.3 mm.

In addition to producing waveform artifacts, the time course of tissueencapsulation of the sensing diaphragm could be estimated by assessingLA pressure waveforms for baseline drift with or without the developmentof artifacts. It was hypothesized that as neoendocardial tissue growsover the sensing diaphragm, measured LA pressure increased due to adrifting baseline caused by tension applied from the tissue capsulecovering the diaphragm through its contiguous connection with the atrialwall. This healing phenomenon may be initiated as early as severalweeks' post implant in animals and starts around 3-4 months in humans.Using the timing of drift to indicate tissue coverage in humans, it wasshown that in a group of 46 heart failure patients with the originalsensor design geometry, about 25% developed the characteristic driftpattern associated with tissue coverage of the sensing diaphragm duringthe first year after implantation. Of 41 similar patients implanted withthe improved geometry sensor, none developed drift.

Pannus formation on devices that traverse the interatrial septum hasbeen observed to start at the portions of the device in contact with theseptum in the region of local tissue injury. Tissue growth progressescontiguously, extending translationally along the external surfaces ofthe device that protrude into each atrial chamber. This pannus growththins as a function of distance from the sites of cardiac contact untilit becomes essentially a monolayer of neoendothelial cells. The processnaturally stops after about 6-12 months in humans. Thereafter, theremaining tissue may remodel but active growth of pannus is completed.From these data, Applicants observed that tissue coverage typicallygrows a distance of about 3 mm from its starting place on the septalwall before stopping or becoming thin enough so as not to impede devicefunction.

Thus, for pannus to cause narrowing of the lumen at the shunt neck, itwould have to extend contiguously from the site of injury on the septumfor some distance to reach the neck. Applicants have determined thattranslational tissue growth over a distance of 3 or more millimetersbecomes much less likely.

Pannus formation affecting the valve leaflets is the most likelystand-alone mechanism that explains all of the untoward observationsseen in human subjects implanted with V-Wave shunts, includingprogressive shunt narrowing, incompetence of the valve withbidirectional flow, and eventual loss of shunt flow with associated lossof clinical efficacy.

Tissue overgrowth affecting the valve leaflets bases and commissures wasthe predominant histopathological finding in the ovine pre-clinicalstudy described above. Gross pathological examination of shuntsimplanted for 3 months showed pannus infiltration extending from theadjacent FO into the valve leaflet bases with thickening of the leafletbodies in 5 out of 6 shunts. In 4 shunts, there was fusion of at least 2of the 3 valve commissures where the leaflet edges were sutured to theshunt frame. Fusion of all 3 commissures was observed in 3 shunts. Onecase showed severe narrowing at the commissures with a luminal area of 4mm² or a 75% area stenosis in comparison to the normal 19.6 mm² lumen atthe device neck. The leaflets were described as semi-pliable orstiffened in 4 out of 6 shunts. In two of the devices, commissuralfusion and leaflet thickening were so pronounced that complete leafletcoaptation could not likely occur during valve closure. In none of thesecases has pannus formation been seen to narrow the shunt neck.

On examination of microscopic sections, pannus thickness tends to begreater on the side of the leaflets facing the atrial septum where theePTFE/leaflet junction was infiltrated with pannus that was contiguouswith the adjoining atrial tissue. Pannus extended from the atrial septumon and around the right atrial edge of the ePTFE skirt and into the baseand commissures of the valve leaflets. At 3 months, the pericardialleaflets showed varying degrees of pannus coverage ranging from mild tomarked. In general, pannus is thickest at the leaflet bases andcommissures, and tapers toward the free edges. In 2 sheep, the pannus onthe leaflets measured 2 to 3 times the original thickness of theleaflets.

The pannus was generally well healed or organized by 3 months. It wascomposed of collagen and proteoglycan matrix surrounding smooth musclecells, fibroblasts and rare focal areas of inflammation withlymphocytes, macrophages, and occasional multinucleated (foreign bodytype) giant cells. The pannus tissue was mostly covered withneoendothelium consistent with near complete healing. No leafletcalcification or thrombi were observed.

Although animal models of cardiovascular devices are limited in theirability to represent human tissue healing responses, the majordifferences are characteristically limited to the temporal duration ofthe response. For example, in a comparative pathology study described inthe publication, “Comparative Pathology of an Implantable Left AtrialPressure Sensor” by Roberts, et al., of a percutaneously implantabletitanium/nitinol-enclosed LA pressure sensor, implanted on theinteratrial septum, it was found that sheep at 1.5 to 8 months andcanines implanted for 1 to 25 months, closely approximated thepathological findings seen in humans implants of 3 to 56 monthsduration. Histology had a similar appearance in humans and animals, andconfirmed that the tissue covering the device was composed of aneoendocardium lined with a neoendothelium. The appearance of theneoendocardial tissue covering the sensor described above was similar towhat is observed with ASD closure devices.

This mechanism of pannus formation preferentially affecting thebioprosthetic valve material compared to the ePTFE encapsulated portionsof the shunt was observed in the human explanted specimen referred toearlier. After 2.5 year of implantation in heart, the 3 pericardialleaflets were severely thickened, immobile, infiltrated at their basesand commissures with pannus resulting in valvular stenosis with areduction in outflow area of 52% relative to the non-obstructed shuntneck. Although this shunt was patent, it would have been incompetent,allowing bidirectional flow, and would have shunted less than half ofthe flow expected for any given pressure gradient.

To further evaluate the tendency of this bioprosthetic valve to becomeinfiltrated with pannus, valved and valveless designs of the V-Waveshunt were implanted by applicants in a non-diseased juvenile ovine(n=9) model. Specifically, this study was designed to highlight theresistance of a valveless, ePTFE encapsulated shunt (n=6) to pannusformation, narrowing and occlusion, relative to the legacy valvedversion previously used in humans (n=3), by creating a highlyproliferative model expected in healthy juvenile sheep where theleft-to-right interatrial pressure gradient was expected to be small. Inthe valveless design, the bioprosthetic valve material and its attachingpolypropylene suture were removed and the ePTFE encapsulation wasextended to cover the entire nitinol frame of the shunt except for thelast 1.5 mm on the RA side where the shunt was coupled to its deliverysystem for deployment. The ePTFE used had an internodal distance of upto 30 microns. At 12 weeks the sheep where euthanized. The grosspathology findings showed that the 3 valved shunts were heavilyinfiltrated with pannus formation, extending from the septum into theregions containing the bioprosthetic leaflets. The leaflets were fused,immobile and highly stenotic leaving only a pinhole opening. The degreeof pannus formation was much exaggeration versus prior experience in theovine heart failure model. Thick pannus extended retrograde contiguouslyfrom the leaflet bases toward the hourglass neck of the shunts. Thepannus growth from the original septal site of injury to the tips of thevalve leaflets exceeded 3 mm in distance. Pannus appeared to growthrough the valve commissures and through the suture holes attaching theporcine pericardial leaflets to the frame and the ePTFE skirt. Pannusformation was associated with mononuclear inflammatory cell infiltratesand multinucleated giant cells.

All 6 of the valveless, ePTFE encapsulated shunts were widely patentwith only minimal pannus formation attaching the FO tissue to theexternal surface of the device. Applicants observed no pannus growingtranslationally more than 3 mm along the external surface of the ePTFEfrom the septum. No visible pannus reached from the septum all the wayinto the lumen portion of either the left atrial entry cone or rightatrial exit cone of the device. The lumina at the necks of all of theshunts were widely patent on gross and microscopic examination. Therewas no evidence of pannus formation permeating through the ePTFEencapsulation into the shunt lumen.

From these combined observations, applicants have determined that lengthof translational pannus growth from the site of healing may be dependenton the type of biomaterial surface. In the case of the ePTFEencapsulated shunt, pannus formation severe enough to interfere withdevice function tends to translate a maximum of about 3 mm from the siteof injury, whereas in the case of the bioprosthetic valve materialtested, the amount of pannus formation and translational length ofpannus tissue growth were exaggerated.

Also, from these data, it is reasonable to expect that the near completeshunt healing seen after 3 months in the juvenile ovine model will bepredictive of the histopathological findings in humans at 9-12 months.Moreover, these gross and microscopic observations, with theiranticipated species-to-species conservation of findings, leads to theconclusion that the healing response in sheep is likely indicative ofthe mechanism causing shunt closure, valvular incompetence, andprogressive stenosis in humans. Thus, there exists a need for a moredurable shunt configuration that maintains luminal patency for extendedperiods of time.

It further would be desirable to provide a shunt for redistributingatrial blood volumes and reducing interatrial pressure imbalances thatreduces the risk of paradoxical embolism caused by emboli transfer fromthe right to left atria.

It also would be desirable to provide an interatrial shunt configurationthat reduces the risk of pannus formation after a prolonged period ofimplantation, where the degree of pannus formation and tissue ingrowthis not strongly dependent on the manner or location in which the shuntis implanted in the FO.

SUMMARY OF THE INVENTION

In view of the foregoing drawbacks of previously-known interatrialshunts, a shunt constructed in accordance with the principles of thepresent invention provides a more durable configuration that maintainsluminal patency for extended periods of time. The inventive shuntfurther enables redistribution of interatrial blood volumes and pressureimbalances while reducing a risk of paradoxical embolism caused byemboli moving through the shunt from the right to left atria.

Shunts constructed in accordance with the principles of the presentinvention also provide greater safety by enhancing long-term patency andreducing the risk of pannus formation after a prolonged period ofimplantation by reducing the impact of the manner in which the shunt isimplanted in the interatrial septum.

In accordance with the principles of the present invention, shuntshaving an anchor and conduct are provided for redistributing atrialblood volumes, in which the shunt dimensions, contours and materialsmaintain long-term patency while reducing the risk of paradoxicalembolism. It is hypothesized that such shunt designs will providereductions in left atrial pressure, relieve pulmonary congestion, andlower pulmonary artery pressure, among other benefits. The inventivedevices are configured for implantation through the atrial septum, andpreferably through the fossa ovalis.

In particular, shunts designed in accordance with the principles of thepresent invention are designed to control LAP by transferring a smallportion of the blood normally flowing from the left atrium to the leftventricle and diverting it instead to the right atrium, thereby modestlyreducing LV end-diastolic filling volume. When the LAP is elevated, theLV operates on a steeper portion of its diastolic compliance curve.Accordingly, even a modest reduction in LV end-diastolic volume leads toa substantial fall in LV end-diastolic pressure. That reduction causes acommensurate reduction in upstream filling pressures including LAP,pulmonary venous pressure, and pulmonary artery pressure. Theanticipated clinical result of these pressure reductions is expected torelieve or even prevent pulmonary congestive symptoms. At smallerinteratrial gradients with less shunting, the effect on LV volume andfilling pressures becomes progressively smaller until it is negligible.As interatrial shunting primarily affects LV filling and not afterload,beneficial effects on lowering end-diastolic pressure are expected,regardless of LV systolic function, for patients with heart failureassociated with reduced ejection fraction (HFrEF) and patients withheart failure and preserved ejection fraction (HFpEF).

In accordance with one aspect of the present invention, the inventivedevices include an anchor configured to be implanted in the interatrialseptum, preferably the FO, and a conduit affixed to the anchor. Theconduit includes a luminal wall defining a lumen, such that the luminalwall comprises a biocompatible material that is resistant to transmuraltissue growth, and that limits translational tissue growth to 3 mm orless from the site of contact to the nearest cardiac structure. In onepreferred embodiment, that anchor may have an hourglass or “diabolo”shaped frame with a neck region adjoining flared end regions, and theconduit may comprise a biocompatible material that encapsulates theframe. The frame, which may be formed of a biocompatible elastically orplastically deformable material, or shape memory material. The devicemay be implanted by forming a puncture through the atrial septum,particularly through the FO, and then percutaneously inserting thedevice therethrough, such that the neck region lodges in the puncture,the first end region extends into the left atrium, and the second endregion extends into the right atrium.

The biocompatible material that may be a polymer, such as expandedpolytetrafluoroethylene (ePTFE), polyurethane, DACRON (polyethyleneterephthalate), silicone, polycarbonate urethane, Ultra High MolecularWeight Polyethylene (UHMWPE) or PTFE. The biocompatible material mayalso be a metal, ceramic, carbon nanotube array or any other suitablematerial known to those familiar with the art that provides the shuntwith the following properties. One purpose of the biocompatible coveringis to form a conduit, with the biocompatible material serving as abarrier to isolate the shunt lumen from the exterior of the conduit.Additionally, the biocompatible material isolates the lumen frompenetration by cellular proliferation (pannus formation) occurring onthe exterior surface of the conduit, where it contacts the septum or FO,which result from the processes associated with device healing. Thebiocompatible material should also impede translational growth of pannusalong the luminal wall of the conduit for more than about 3 mm from thesite of contact with any cardiac structure.

The concept of having a separate anchor to provide shape and a conduitto provide isolation, which when combined comprise the shunt, is solelyfor the general convenience of developing practical device embodiments.It will be apparent to one skilled in the art that a shunt device withthe requisite shape, expansion and covering characteristics could beconstructed from a single unitary material that serves as both anchorand conduit. For example, one such embodiment may comprise injectionmolded silicone rubber that forms a single piece self-expanding shunt.Also, superelastic polymers are under development that have mechanicaland biocompatible properties comparable to nitinol alloys. Thus, theanchor or frame used interchangeably throughout this specificationshould be considered in the general sense to refer to any composition oflinked physical members that contribute in substantial part to the shuntdevice's shape and other physical properties that govern the shunt'stransition from pre-deployment constrainment to the expanded anddeployed state where it is in contact with tissue. All of the shuntdevice embodiments described in this patent application can beunderstood in terms of component parts (anchor and conduit) or as aunitary device with certain specified physical properties includingshape geometry in pre-and post-deployment states and biocompatiblesurface properties.

The cross-sectional profile of shunt lumen perpendicular to its axis offlow may be round, oval, rectangular, or any other regular or irregularpolygonal shape. The cross-sectional profile may vary from one shape toanother along the axis of flow, which may be a straight line or may becurvilinear. The cross-sectional profile may rotate along the axis offlow. The shunt may have a single lumen or there may be a plurality oflumina.

In one aspect of the present invention, a device for regulating blooddistribution between a patient's left atrium and right atrium comprisesan anchor having a neck region joining first and second end regions, theneck region configured to engage the fossa ovalis of the patient'satrial septum; and a conduit affixed to the anchor so that the conduitextends into the right atrium by a distance selected to reduce the riskof paradoxical embolism. The conduit preferably comprises abiocompatible material that limits (or inhibits excessive) tissueingrowth into the lumen of the conduit. The anchor and conduit areconfigured to accommodate endothelial or neointima layer growth up to athickness of about 0.6 mm or less, so as to render such material inert,inhibit hyperplasia, and substantially inhibit obstruction of the flowpath through the device.

In one preferred embodiment, the anchor comprises hourglass-shaped framehaving a plurality of circumferential struts interconnected bylongitudinal struts that, when deployed, form first and second flaredend regions connected by a neck. In some embodiments, when the shunt isdeployed across the patient's atrial septum, the first flared end regionprotrudes 3 to 10 mm into the left atrium beyond the surface of the leftseptal wall. The second flared end region may protrude 5 to 10 mm intothe right atrium beyond the surface of the right septal wall. The neckhas an inner diameter of 4 to 8 mm, where preferably the inner diameteris in a range of 5 to 6.5 mm. The first flared end region preferably hasa diameter selected in the range of between 10 and 20 mm, and the secondflared end region preferably has a diameter selected in the range ofbetween 9 and 15 mm. The first and second flared end regions eachpreferably flare outward from the longitudinal axis of the shunt by anamount selected from between about 25 to 60 degrees, although suchangles may be different for each of the first and second flared regions.For example, in one embodiment, the steepest part of the outer surfaceof the first flared end region is at an angle of approximately 40degrees relative to the longitudinal axis of the device, while thesteepest part of the outer surface of the second flared end region maybe at an angle of approximately 37.5 degrees relative to thelongitudinal axis of the device.

In preferred embodiments, the shunt is configured to transition betweena collapsed state suitable for percutaneous delivery and an expandedstate when deployed across the patient's fossa ovalis, such that theshunt assumes an hourglass configuration in the expanded state. Thehourglass configuration may be asymmetric. The shunt may be configuredfor implantation through a portion of the fossa ovalis, away from thesurrounding limbus, inferior vena cava, and atrial wall.

Methods of treating a subject with heart pathology also are provided,including providing a shunt having first and second end regions and aneck region disposed therebetween; deploying the shunt across a puncturethrough the subject's interatrial septum, preferably through the FO,such that the neck region is positioned in the puncture with the firstend region disposed in the left atrium, and the second end regiondisposed in the right atrium, such that flow through the deviceredistributes blood between the left atrium and the right atrium throughthe device when the left atrial pressure exceeds the right atrialpressure.

Subjects with a variety of heart pathologies may be treated with, andmay benefit from, the inventive device. For example, subjects with heartfailure and pulmonary congestion, reducing the left atrial pressure andleft ventricular end diastolic pressure may provide a variety ofbenefits, including but not limited to decreasing pulmonary congestion;decreasing pulmonary artery pressure; increasing ejection fraction;increasing fractional shortening; and decreasing left ventricle internaldiameter in systole. Other heart pathologies that may be treated includemyocardial infarction, which may be treated by deploying the deviceduring a period immediately following the myocardial infarction, e.g.,within six months after the myocardial infarction, or within two weeksfollowing the myocardial infarction, to reduce myocardial remodeling.

Patients with pulmonary arterial hypertension (PAH) due to idiopathiccause or associated with other disorders such as connective tissuediseases, drugs or toxins, HIV infection, portal hypertension, orcongenital heart disease have been shown to benefit from atrialseptostomy procedures that cause interatrial shunting from the right tothe left atrium (right to left shunt). These procedures include blade orballoon septostomy or placement of devices such as uncovered diabolostents or fenestrated atrial septal occlusion devices. It will beapparent to persons of skill in the art that the embodiments alreadydescribed and other preferred embodiments described in this patentspecification are applicable to treating patients with PAH.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1A to 1C are, respectively, perspective, end and side views of apreferred embodiment of a shunt constructed in accordance with theprinciples of the present invention.

FIG. 2 is a side view of an alternative embodiment of a shunt of thepresent invention having a cutout in its polymeric encapsulation tosecure the shunt to a delivery system.

FIG. 3 is a perspective view of another alternative embodiment of ashunt of the present invention having an alternative cutout in itsencapsulation.

FIGS. 4A and 4B are, respectively, end and side views of a furtheralternative embodiment of a shunt constructed in accordance with theprinciples of the present invention having eyelets that engage adelivery system.

FIGS. 5A and 5B are plan views of further alternative embodiments ofanchors suitable for use in the inventive shunt, cut along line 5A-5Aand 5B-5B, and unrolled to a flat configuration.

FIG. 6 is a graph comparing theoretical flows through a shunt designhaving a Venturi contour with 5 mm and 6 mm diameter orifices comparedto theoretical flows obtained using orifice plate-type devices.

FIGS. 7A and 7B are, respectively, a plan view of the right atrial sideof the atrial septum, illustrating implantation of a shunt through aportion of the fossa ovalis, and a perspective view of an embodiment ofthe shunt of FIGS. 1A-1C positioned in the fossa ovalis of the atrialseptum.

FIGS. 8A and 8B schematically depict pannus formation on anhourglass-shaped embodiment of the shunt of the present inventionpositioned in the fossa ovalis orthogonal to the atrial septum wall,immediately after implantation and after pannus formation.

FIGS. 9A and 9B schematically depict pannus formation on anhourglass-shaped embodiment of the shunt of the present inventionpositioned in the fossa ovalis non-orthogonal to the atrial septum wall,invention immediately after implantation and after pannus formation.

FIGS. 10 through 15 depict various alternative embodiments of shuntsconstructed in accordance with the principles of the present invention.

FIGS. 16A and 16B are, respectively, side and end views of anchorsuitable for a further alternative shunt embodiment havingself-expanding flexible arms that form a filter over the right atrialside of the conduit.

FIG. 17 is a graph comparing theoretical flows through shunt designsconstructed in accordance with the principles of the present inventioncompared to a previously known valved shunt design.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Interatrial shunts are provided for redistributing interatrial bloodvolumes and reducing left atrial pressure, which may be advantageous intreating subjects suffering from heart failure (HF) or other disordersassociated with elevated left atrial pressure. A preferred embodiment ofthe inventive device includes an anchor, which may be an hourglass or“diabolo” shaped stent or frame, and a conduit, formed by encapsulatingthe frame in a synthetic biocompatible material. The shunt is configuredto be lodged securely within a passage formed in the atrial septum,preferably the fossa ovalis, and provides one-way blood flow from theleft atrium to the right atrium, when blood pressure in the left atriumexceeds that on the right.

Referring now to FIGS. 1A to 1C, an illustrative embodiment of shunt 10of the present invention is described. Shunt 10 generally comprisesanchor 12 having three regions: flared or funnel-shaped end region 14,flared or funnel-shaped end region 18, and neck region 16 disposedbetween end regions 14 and 18. Neck region 16 is configured to lodge ina puncture formed in the atrial septum, preferably in the fossa ovalis.Flared end regions 14 and 18 are configured to partially engage andprotrude beyond the right and left sides, respectively, of the atrialseptum when implanted. Shunt 10 further comprises a conduit,illustratively formed by encapsulating anchor 12 with biocompatiblematerial 20 that covers all or substantially all of anchor 12 to form aconduit defining a lumen or interior passageway 22.

Flared region 14 is configured to be disposed in the right atrium, whileflared region 18 is configured to be disposed in the left atrium. In oneembodiment, anchor 12 includes six longitudinal struts 24 interconnectedby five circumferential struts 26 a-26 e. Longitudinal struts 24 preventforeshortening of the anchor during expansion, while the sinusoidal orserpentine bends in circumferential struts 26 a-26 e permit the anchorto transition between a radially collapsed substantially cylindricaldelivery state to an expanded, flared, deployed state as illustrated inFIGS. 1A to 1C. As depicted in the figures, a conduit is formed bybiocompatible material 20 that encapsulates the entirety of neck 16,flared end region 18, and flared end region 14. Biocompatible material20 preferably is affixed to anchor 12 using a suitable biocompatibleadhesive or by sandwiching the anchor between inner and outer layers ofbiocompatible material using sintering techniques.

In a preferred embodiment, anchor 12 comprises a self-expandingmaterial, such as a shape memory alloy, and circumferential struts 26a-26 e are treated to expand a predetermined amount when deployed, sothat together with encapsulation 20, lumen 22 has a contour that permitssubstantially laminar flow between flared end section 18 (in the leftatrium) and flared end section 14 (in the right atrium). Sinusoidal orserpentine bends 28 in circumferential struts on flared end region 14preferably are 180 degrees out of phase with the sinusoidal orserpentine bends 28 in neck region 16 and flared end region 18, so thatthe sinusoidal or serpentine bends do not extend beyond the ends oflongitudinal struts 24 in either the collapsed delivery state ordeployed state.

Anchor 12 may comprise a biocompatible metal framework or laser-cutsolid metallic tube made from nitinol, titanium alloy, cobalt chromiumalloy, MP35n, 316 stainless steel, L605, Phynox/Elgiloy, platinumchromium or other biocompatible metal such as are known to persons ofskill in the art. While a preferred embodiment employs a shape memoryself-expanding alloy, anchor 12 alternatively may comprise anelastically or plastically deformable material, e.g., balloonexpandable, or may be a shape memory alloy that responds to temperaturechanges to transition between contracted delivery and expanded deployedstates. The surface finish applied to the material of the anchor may beselected to control the distance, thickness, composition and/or growthpattern of pannus formation, e.g., the external surfaces of anchor 12may be electro-polished.

In accordance with the principles of the present invention, the radialdimensions, axial lengths and contours of neck region 16 and flared endregions 14 and 18 preferably are selected to provide laminar flowthrough the interior of the shunt, to reduce the formation of eddycurrents when implanted, and thus inhibit thrombus formation; to inhibitpannus formation that could obstruct the neck region; to promote tissueingrowth around the exterior of the neck region to secure the shuntagainst migration; to provide a desired rate of blood flow between theleft and right atria at physiological pressure differentials; and toprevent retrograde paradoxical embolization.

Biocompatible material 20 forming the conduit preferably is resistant tothe transmural and translational ingrowth of pannus material having atissue thickness greater than 0.6 mm. For example, in experimental ePTFEvascular grafts, those with a 60-micron internodal distance showedrapid, transmural infiltration with proliferating smooth muscle cellsand granulation tissue, whereas ePTFE grafts with a 30-micron internodaldistance were observed to develop only a slow growing, thin sheet ofendothelium that advanced only a few millimeters into the graft lumenfrom the adjacent artery. Porous polyester fabric coverings employed onsome atrial septal defect (“ASD”) occlusion devices would be poorchoices for use in the shunt of the present invention, because suchmaterials become completely enmeshed with penetrating fibrotic tissue.It is expected that when shunt 10 comprises anchor 12 made of, forexample, electro polished nitinol, and biocompatible material 20 may bean inert polymer such as ePTFE with an internodal distance of 30 micronsor less, or is PTFE, such that pannus will grow to a thickness nogreater than about 0.6 mm after extending translationally a distance of3 mm from the site of contact with the Foramen Ovalis (“FO”) tissue. Insuch cases, interior lumen of the conduit is not expected to narrowbeyond a total of 1.2 mm from its original diameter and the neck. Forthe purposes of this patent the term “luminal narrowing” shall bedefined as a loss of minimal shunt lumen diameter of greater than 25%and the term “luminal obstruction” is defined as total (100% loss oflumen diameter) blockage of the lumen to the flow of blood.

In the preferred embodiment depicted in FIGS. 1A to 1C, anchor 12 has anhourglass shape formed of a shape memory metal, e.g., nitinol, or anyother suitable material known in the art. Circumferential struts 26 a-26e and longitudinal struts 24 preferably comprise a unitary construction,that is, entire anchor 12 is laser cut from a tube of shape memorymetal. Biocompatible material 20 may comprise, for example, a sheet of apolymer such as expanded polytetrafluoroethylene (“ePTFE”),polytetrafluoroethylene (“PTFE”,) silicone, polycarbonate urethane,DACRON (polyethylene terephthalate), Ultra High Molecular WeightPolyethylene (UHMWPE), or polyurethane. The biocompatible material mayalso be a metal, ceramic, carbon nanotube array or any other suitablebiocompatible material. For example, biocompatible material 20 maycomprise ePTFE with an up to 30-micron internodal distance, and may beapplied as inner and outer layers sintered together to form a unitaryconduit. Alternatively, biocompatible material 20 may be applied to theinner lumen and the outside of the anchor using electrospinningtechniques. Other methods of encapsulation and other suitable polymersthat prevent transmural ingrowth of pannus tissue may alternatively beused, as will be understood by one skilled in the art. Bare metalregions of anchor 12, and any other regions of the anchor, optionallymay be electropolished or otherwise treated to inhibit thrombusformation using known methods.

As noted above, neck 16 of shunt 10 preferably is configured forimplantation through the fossa ovalis of the atrial septum, and morepreferably near or at the central portion of the fossa ovalis. As knownto those skilled in the art, the fossa ovalis is a thinned portion ofthe atrial septum formed during fetal development of the heart, whichappears as an indent in the right side of the atrial septum and issurrounded by a thicker portion of the atrial septum. While the atrialseptum itself may be several millimeters thick and muscular, the fossaovalis may be only approximately one millimeter thick, and is formedprimarily of fibrous tissue.

In some embodiments of the present invention, shunt 10 may beasymmetrically shaped to take advantage of the natural features of theatrial septum near the fossa ovalis, and to provide suitable flowcharacteristics. For example, in a preferred embodiment, the anchorcomprises an hourglass or diabolo shape where a LA entry funnelresembles a conical-shaped nozzle and a RA exit funnel is “bell” shaped,with the wide mouth lumen of the bell at the RA exit port in the RA. Thenarrow entrance to the bell-shaped exit funnel connected to the orificeof the neck region may be configured to approximate the curved surfaceof a parabola. This type of convergent-divergent nozzle resembles theshape of a classical de Laval nozzle used in rocket engines. Left toright flow is largely governed by the smooth convergence of streamlinesin the entry cone and the divergence of streamlines exiting the bell.Such a nozzle configuration is very efficient in the forward flowdirection having a discharge coefficient resembling a classic venturitube, e.g., 0.95-0.98.

Referring now to FIG. 1C, points B and C are located on the leftmostcircumferential strut 26 e, which defines the LA entry port. Points Aand D are located on circumferential strut 26 d along the LA entryfunnel proximal to strut 26 e. Points H and E are located oncircumferential strut 26 b along the RA exit funnel, and points G and Fare located on circumferential strut 26 a, which defines the RA exitport. In preferred embodiments, the diameter of lumen 22 in the neckregion of the shunt orifice ranges from 5 to 6.5 mm. The portion of theshunt crossing the FO, bounded by points ADEH may be 3 mm in axiallength but may be extended up to 10 mm in patients with a thicker FO.The diagonal length between points AB, CD, EF, and/or GH is preferably≥3 mm so that pannus cannot grow translationally inward from the ends ofthe shunt and thus obstruct neck region 16. In addition, the horizontalcomponent length between points AB, CD, EF, and/or GH is preferably ≤15mm, to avoid interference with existing cardiac structures whenimplanted. In accordance with another aspect of the invention, it hasbeen determined that providing a length of segments EF and GH generallygreater than 5 mm is expected to ensure that the end region that extendsinto the right atrium is disposed generally out of the flow path ofblood returning from the inferior vena cava, which is most likely tohave entrained emboli that could cause paradoxical embolization.Truncated funnel cones bounded by ABCD and/or EFGH may have volumes ≤2ml.

Other embodiments of the shunt of the present invention may includeanchors with different combinations and configurations ofcircumferential ring and axial strut elements. Specifically, suchembodiments, may have more or less than 6 longitudinal struts 24 andmore or less than five circumferential struts 26 a-26 e. Theseconfigurations may yield other shunt lumen geometries. In anotherembodiment, anchor 12 may be made of a self-expanding polymer.Alternatively, the anchor need not be self-expanding, and may be madefrom a plastically deformable biocompatible metal such as 316 Lstainless steel, cobalt chromium alloys, or any other such suitablematerials known to those skilled in the art. Such a deformable shuntanchor may be delivered by an expanding member, such as a balloon, thatis configured to achieve the desired luminal geometry. The deformableanchor may be designed to expand prismatically or at certain localizedsites where ductile hinges are configured for more selected expansion astaught by U.S. Pat. No. 6,242,762 to Shanley, the contents of which areincorporated by reference herein.

Referring now to FIG. 2, an alternative embodiment of a shuntconstructed in accordance with the principles of the present inventionis described. Shunt 30 includes anchor 31 is similar in construction tothat described for the embodiment of FIGS. 1A-1C, and has flared endregions 32 and 33 and neck region 34. When implanted in a patient'sinteratrial septum, flared end region 32 is disposed in the patient'sright atrium, while flared end region 33 is disposed in the patient'sleft atrium, with neck region 34 situated in a passage formed in theinteratrial septum. Anchor 31 includes longitudinal struts 35 andcircumferential struts 36 a-36 e, and is encapsulated by biocompatiblematerial 37. Anchor 31 may comprise a self-expanding or plasticallydeformable material as described herein above.

Shunt 30 of FIG. 2 differs from the previous embodiment in thatbiocompatible material 37, for example ePTFE, includes cutout 38adjacent to circumferential strut 36 a. Cutout 38 may extend proximallyfrom circumferential strut 36 a for a distance of 0.5 mm to 2 mm, andmore preferably about 1 mm, to permit circumferential strut 36 e to bereleasably engaged with a delivery system during deployment, forexample, hooks, as described by Yacoby in US Patent Publication2014/0350565. Biocompatible material 37 may be trimmed manually ormechanically from circumferential strut 36 a to create cutout 38 or bylaser-cutting. In this manner, shunt 30 may be positioned andrepositioned in a passage formed in the interatrial septum until theclinician is satisfied with the device placement, before being released.In a preferred embodiment, the conduit formed by biocompatible material37 extends a distance of at least 3 mm beyond neck region 34 into flaredend region 32, to ensure that pannus cannot grow translationally alongluminal wall far enough to partially occlude the flow area of neckregion 34. Additionally, flared end region 32 extends a distance of atleast 5 mm into the right atrium when implanted in the interatrialseptum to ensure that the entry of flared end region 34 is generally notaligned with flow paths generated by blood entering the right atriumfrom the inferior vena cava, thereby reducing the risk that embolicarried from the lower extremities into the right atrium will causeparadoxical embolism by passing through shunt 30.

With respect to FIG. 3, another alternative embodiment of inventiveshunt is described. Shunt 40 includes anchor 41 having flared endregions 42 and 43 joined by neck region 44, as described for thepreceding embodiments. Anchor 41 includes longitudinal struts 45 joinedby circumferential struts 46 a-46 e and biocompatible material 47, forexample a thin layer of ePTFE or other suitable material as describedabove. Shunt 40 differs from the embodiment of FIGS. 1A to 1C in thatthe polymeric encapsulation includes cutouts 48 on alternating peaks ofthe sinusoidal bends formed by circumferential strut 46 a that permit adelivery device to releasably engage shunt 40. Shunt 40 also includesskirt 49 of biocompatible material that extends beyond circumferentialstrut 46 e. In a preferred embodiment, cutouts 48 include circularsectors having angles in the range of 60° to 180°, more preferably 120°,such that largest distance between the edge of the polymericencapsulation and circumferential strut 46 a is in the range of 0.5 to 2mm, and more preferably 1 mm. The configuration of cutouts 48 of shunt40, which may be laser cut, advantageously maximize the encapsulatedarea of the shunt while still enabling proper engagement to the deliverysystem hooking mechanism. As will be apparent to those skilled in theart, other possible cutting patterns or methods may be employed.

Referring now to FIGS. 4A and 4B, another embodiment of a fullyencapsulated hourglass shunt constructed in accordance with theprinciples of the present invention is described. Shunt 50 includesanchor 51 having end regions 52 and 53 joined by neck region 54. Anchor51 has longitudinal struts 55 coupled to circumferential struts 56 a-56e as described for preceding embodiments, and includes a conduit formedof biocompatible material 57 as also described hereinabove. Shunt 50differs from the embodiment of FIGS. 1A to 1C in that alternatinglongitudinal struts 55 include elongated portions 58 having eyelets 59for engagement with a delivery system extending from right atrial endregion 52. Shunt 50 may have between 2 to 6, and preferably 3 elongatedportions 58 and eyelets 59 left as bare-metal, i.e., without polymericencapsulation. Elongated portions 58 preferably are short, protruding aminimum additional distance into the right atrium or alternatively areconstructed to bend into the right atrium RA exit port on release fromthe delivery system to serve as filter to block paradoxical emboli frompassing into the lumen of the conduit at end region 52. An alternativeapproach that also filters the size of emboli is to construct the shuntwith a plurality of passageways or lumina that transport blood inparallel such that the total cross-sectional area of all the of thepassageways conserves the flow characteristics needed for adequateshunting to achieve the redistribution of blood between the atria asdesired.

With respect to FIGS. 5A and 5B, further alternative embodiments of ananchor suitable for constructing a shunt in accordance with one aspectof the present invention are described. Anchor 60 is similar in designto anchor 51 of the embodiment of FIGS. 4A and 4B, and includeslongitudinal struts 61 joined to circumferential struts 62 a-62 e, whichinclude sinusoidal bends. Accordingly, anchor 60 when expanded includesflared end regions joined by a neck region to form a generally hourglassshape, while longitudinal struts 61 prevent foreshortening, i.e., axialshrinkage, during deployment. For purposes of illustration, anchor 60 asdepicted in FIG. 5A is shown cut along one of longitudinal struts 61(along line 5A-5A) and flattened, although the anchor preferably is cutfrom a tubular material. As for preceding embodiments, anchor 61includes a polymeric encapsulation that forms a conduit, omitted forclarity from FIG. 5A, that covers the anchor between circumferentialstruts 62 a and 62 e. Anchor 60 includes elongated portions 63 andeyelets 64 that extend into the right atrium when the shunt is employed.In accordance with one aspect of the invention, alternating eyelets 64include radiopaque markers 65, for example made of platinum iridium,gold, tantalum, or any other similar suitable material, which enhancevisualization of the shunt under fluoroscopy. Eyelets 64 that do notaccommodate radiopaque markers 65 permit the shunt to be releasableengaged by a delivery system for percutaneous transluminal delivery.

In FIG. 5B, anchor 66 is similar in design to anchor 60 of theembodiment of FIG. 5A, except that in this embodiment circumferentialstruts 67 a-67 e having sinusoidal bends that extend betweenlongitudinal struts 68 all face in the same direction. Anchor 66additionally includes eyelets 69 that extend from alternatinglongitudinal struts 68 for use in releasably coupling the shunt to apercutaneous transluminal delivery system. One advantage of this designis that retrieval of a self-expanding shunt using anchor 66, by itsdelivery system when halfway deployed or fully deployed, requires lesspull-back force to collapse the shunt than the embodiment of FIG. 5A. Asin preceding embodiments, anchor 66 when expanded includes flared endregions joined by a neck region to form a generally hourglass shape,while longitudinal struts 68 prevent foreshortening during deployment.For purposes of illustration, anchor 66 as depicted in FIG. 5B is showncut along one of longitudinal struts 68 (along line 5B-5B) andflattened, although the anchor preferably is cut from a tubularmaterial. Anchor 66 further includes a conduit formed by encapsulatingthe anchor with a biocompatible material, omitted for clarity from FIG.5B, that covers the anchor between struts 67 a and 67 e.

In accordance with one aspect of the present invention, an interatrialhourglass-shaped shunt with flow characteristics resembling a venturitube and a discharge coefficient of approximately 0.96-0.97 may have aminimal neck orifice inner diameter ranging from 5 mm to approximately6.5 mm. Having a somewhat larger orifice diameter, within this range,e.g. 6.0 mm, will support approximately 35% more flow for any givenpressure gradient compared with a 5.1 mm shunt, as shown in FIG. 6. Thismay not only create improved hemodynamic conditions but provideadditional benefit in maintaining shunt flow should some shunt narrowingdue to pannus ingrowth occur during device healing.

In accordance with another aspect of the invention, various nozzlegeometries with high discharge coefficients relative to an orifice-plategeometry advantageously may be used to provide laminar flow through theshunt. These include but are not limited to various variations ofventuri tubes, conical convergent nozzles (with convergence angles from20 to 80 degrees), cylindrical convergent nozzles, and the Addy typenozzle with a convergent curved entrance wall leading to a length ofcylindrical tubing having a diameter equivalent to the orifice diameter.The latter two appear similar in appearance to the horn of a trumpet. Inanother preferred embodiment, the shunt lumen may be a cylindrical tubewith no or minimal dilation at the entry or exit ports.

The cross-section of lumen 22 (see FIG. 1B) need not be circular and/orthe lumen need not be coaxial with a straight horizontal line axis whenviewed longitudinally. Although these latter geometries may be difficultto deliver through catheters with circular luminal cross-sections, theymay be constrained to such catheter lumens and expand into non-circularcross-sectional or curved longitudinal geometries upon deployment. Otherpreferred embodiments include any combination of entry, orifice, andexit geometries where the exiting jet vena contracta cross-sectionalarea is 70% or greater compared with the minimal orifice area, over therange of physiological interatrial pressure gradients, thereby having ahigher discharge coefficient than an orifice-plate.

A shunt with a single LA conical entry funnel, with an hourglass-shapedlumen, or with a tubular lumen, having a discharge coefficient of 0.70or larger, generally has a longer tunnel of entrained flow by nature ofits longer length, typically 6 to 30 mm long, versus an orifice-platemesh type shunt, which may be defined by the thickness of the FO itselfand is typically shorter than 6 mm, e.g., 3 mm or less. For paradoxicalembolization to occur, i.e., for a paradoxical embolus to embolize fromthe heart into the systemic arterial circulation, the paradoxicalembolus must pass completely or nearly completely through the shunt.Emboli may be propagated by their residual kinetic energy against aleft-to right gradient or when there is no gradient, or may be carriedalong when a reversed pressure gradient creates right to left bulk flow.Depending on the relative magnitude of the kinetic energy of the embolusand the bulk flow directional status, a longer lumen shunt will tend topass fewer emboli compared to an orifice-plate shunt with a shorterlumen. This is likely to be the case in the presence of normal left toright bulk flow or when there is zero net flow. This is also likely tobe true during very transient pressure gradient reversals, such asduring a cough. Therefore, in another preferred embodiment, a shunt witha flow lumen length of 6 to 30 mm, or more typically 10 to 15 mm, byvirtue of its increased lumen length, will have less tendency forparadoxical embolization than an orifice-plate mesh shunt.

Referring now to FIG. 7A, a preferred location for implanting shunt 10of FIGS. 1A-1C of the present invention is described. FIG. 7A is a planview of the right atrial side of atrial septum 70, includingimplantation site 71 located at a central position of fossa ovalis 72.Preferably, implantation site 71 is selected so that the shunt may beimplanted spaced apart from the surrounding limbus 73, inferior venacava (IVC) 74, and atrial septum 75. For example, as shown in FIG. 7B,flared end region 14 is configured to be implanted in right atrium 76and may be tapered so as to have a more cylindrical shape than doesflared end region 18, which is configured to be implanted in left atrium77. The more cylindrical shape of flared end region 14 may reduce orinhibit contact between flared end region 14 and limbus 73 of fossaovalis 72, that is, between flared end region 14 and the prominentmargin of the fossa ovalis, while still anchoring device 10 acrossatrial septum 75. The more cylindrical shape of flared end region 14further may reduce or inhibit contact between flared end region 14, andthe right side of atrial septum 70, as well as ridge 77 separating thecoronary sinus from the IVC 74 (shown in FIG. 7A but not FIG. 7B).

Still with respect to FIG. 7A, a preferred location for shuntimplantation may be slightly anterior to the centerline of the long axisof the fossa ovalis, i.e., located on the right hand side of the ovale.This location leaves potential space in the upper left quadrant(posterior-superior) of the fossa, which has been found to be optimalfor crossing the fossa to perform structural heart disease procedures onthe mitral valve, including edge-to-edge repair with MitraClip®transcatheter mitral valve repair system offered by Abbott, Abbott Park,Ill. and mitral annuloplasty with Cardioband, offered by Valtech Cardio,Or Yehuda, Israel. This preferred location also leaves potential spacein the lower left quadrant (posterior-inferior) of the fossa, which hasbeen found to be optimal for crossing the fossa to perform structuralheart disease procedures to occlude the left atrial appendage. A shuntwith an hourglass shape that occupies the smallest possible location onthe fossa, as described herein, facilitates these other procedures.

Again, referring to FIG. 7B, shunt 10 preferably is configured so as toavoid imposing significant mechanical forces on atrial septum 75, thusallowing the septum to naturally deform as the heart beats. For example,the thicknesses of muscular areas of septum 75 may change by over 20%between systole and diastole. It is believed that any significantmechanical constraints on the motion of atrial septum 75 in such areaswould lead to the development of relatively large forces acting on theseptum and/or on atrial tissue that contacts shunt 10. Such forces couldinvoke an inflammatory response and/or hyperplasia in the atrial septumtissue, and possibly cause shunt 10 to eventually lose patency. However,by configuring shunt 10 so that neck region 16 may be implanted entirelyor predominantly in the fibrous tissue of the fossa ovalis 72 with asmall footprint, the hourglass shape of shunt 10 is expected to besufficiently stable so as to be retained in the septum, while reducingmechanical loads on the surrounding atrial septum 75. Tissue ingrowthfrom atrial septum 75 in regions 78 may further enhance binding of shunt10 to the septum. Preferably, there should be a substantial rim of fossaaround the shunt after implantation, e.g., for a thickness of 1-2 mm, asdepicted in FIG. 7B.

Also, because neck region 16 of shunt 10 is significantly narrower thanflared end regions 14 and 18, shunt 10 will “self-locate” in a puncturethrough atrial septum 75, particularly when implanted through the fossaovalis, with a tendency to assume an orientation where its longitudinalaxis is substantially orthogonal to the FO. In some embodiments, neckregion 16 may have a diameter suitable for implantation in the fossaovalis, e.g., that is smaller than the fossa ovalis, and that also isselected to inhibit blood flow rates exceeding a predeterminedthreshold. Neck region 16 preferably provides a passage having adiameter between about 4 and about 7 mm, and more preferably betweenabout 5 mm and about 6.5 mm. For example, diameters of less than about 4mm may in some circumstances not allow sufficient blood flow through theshunt to decompress the left atrium, and may reduce long-term patency ofthe shunt. Conversely, diameters of greater than about 7 mm may allowtoo much blood flow, resulting in right ventricular volume overload andpulmonary hypertension. Preferably, the effective diameter at thenarrowest point in shunt 10 is about 5 mm to 6.5 mm.

The diameters of flared end regions 14 and 18 further may be selected tostabilize shunt 10 in the puncture through atrial septum 45, e.g., inthe puncture through fossa ovalis 72. For example, flared end region 18may have a diameter of 10 to 20 mm at its widest point, e.g., about 13to 15 mm; and flared end region 14 may have a diameter of 9 to 15 mm atits widest point, e.g., about 9 to 13 mm. The largest diameter of flaredend region 14 may be selected so as to avoid mechanically loading thelimbus of the fossa ovalis 72, which might otherwise cause inflammation.The largest diameter of flared end region 18 may be selected so as toprovide a sufficient angle between flared end regions 14 and 18 tostabilize shunt 10 in the atrial septum, while limiting the extent towhich flared end region 18 protrudes into the left atrium (e.g.,inhibiting interference with flow from the pulmonary veins), andproviding sufficient blood flow from the left atrium through neck region16.

In accordance with the principles of the present invention, the lengthof end region 14 is selected to protrude into the right atrium by adistance sufficient to inhibit tissue ingrowth that may otherwiseinterfere with the operation of shunt 10. Applicants have observed thattissue ingrowth inwards along an impermeably membranes of specifiedbiomaterials from the end that contacts tissue generally stops afterabout 3 mm. Accordingly, to ensure that tissue ingrowth from the ends ofthe conduit does not extend into and partially occlude the flow area ofneck region 16, the distance R between the narrowest portion of neckregion 16 and the end of region 14 should be at least 3 mm plus half ofthe thickness of the septal region, i.e., fossa ovalis, contacting theexterior of shunt 10. Assuming that the fossa ovalis has a thickness ofabout 3.0 mm, then the minimum distance R should be about 4.5 mm, basedon applicants' observations. Likewise, end region 18 preferably does notsignificantly engage the left side of atrial septum 75, so that distanceL also preferably is at least 4.5 mm. Due to patient-to-patientvariability in the thickness of the FO, e.g., due to the patient'sgeneral health and age, and because neck region 16 may not be preciselyaligned with the mid-point of the FO, each distances R and L preferablyfall within a range of 3 to 6 mm. Accordingly, for some embodiments, theoverall dimensions of shunt 10 may be about 9-12 mm long (L+R, in FIG.7B) to prevent tissue ingrowth from the ends of the conduit, i.e., endregions 14 and 18, from partially occluding neck region 16.

In another preferred embodiment, regardless of the geometrical shape ofthe conduit, there should be a minimum of 3 mm of material resistant totranslational tissue growth, i.e., extending inward from the ends of theend regions to accommodate neoendocardial tissue growth over the shuntsurfaces starting from a location in contact with the atrial septum,such that tissue growth cannot reach the orifice (site of minimaldiameter of the shunt lumen or cross-sectional area of lumen 22 shown inFIG. 1B). With this preferred embodiment, the minimal orifice diameterof an interatrial shunt device will be rendered largely unaffected bypannus formation. In another preferred embodiment, there should be aminimum of 3 mm of conduit length for neoendocardial tissue to grow overthe shunt luminal surfaces starting from a location in contact with theatrial septum, before reaching the entrance or exit port sites of theshunt lumen. With such an embodiment, there is even less potential forpannus to encroach the shunt lumen.

Referring now to FIGS. 8A and 8B, the expected healing response invokedby implanting shunt 10 of FIGS. 1A-1C orthogonally across the FO isdescribed, while FIGS. 9A and 9B correspond to implantation of the shuntnon-orthogonally so that an outer surface of the LA entry cone contactsthe atrial septal tissue. FIGS. 8A and 9A depict positioning of theshunts immediately post implantation, while FIGS. 8B and 9B depict shuntpositioning after the completion of the healing phase.

In each of FIGS. 8A and 8B, the FO is shown as bowed towards the RA andconcave towards the LA. In patients with dilated cardiomyopathy orrestrictive physiology, including most patients with left ventricularfailure, regardless of etiology, the FO portion of the interatrialseptum generally is bowed toward the right atrium. This gives the LA agenerally concave or near hemispherical shape in the region centered onthe FO. Conversely, the RA side of the FO is generally convex in shape.This orientation of the FO was confirmed by echocardiography (n=178examinations) in the 38 patients implanted with the V-Wave Nitzan-typevalved shunt discussed in the Background of the Invention portion ofthis specification. In measurements of more than 100 patients exhibitingheart failure with preserved ejection fraction (HFpEF), the LA volumegenerally averaged 85 ml with a minimum volume of 54 ml, while for alike number of patients exhibiting heart failure with reduced ejectionfraction (HFrEF), the LA volume generally averaged 104 ml with a minimumvolume of 71 ml. Although the LA is often approximated by a sphere or anellipsoid, there are frequently exceptions to this, for example, wherethe LA appears squashed when viewed in its anterior-posterior dimension.Although not specifically quantified, the RA appeared to be similar insize to the LA.

Although exceptions to RA bowing of septal anatomy occur, they generallydo so in the presence of isolated right ventricular failure or severepulmonary hypertension in the absence of left ventricular dysfunction ormitral valve disease, e.g. as occurs in pulmonary arterial hypertension(PAH). In those instances, RA pressure tends to exceed LA pressurecausing the FO to bow in the opposite direction toward the LA. Suchpatients generally would derive no clinical benefit from left-to-rightinteratrial shunting. However, patients with severe pulmonaryhypertension in the absence of left-sided heart failure may benefit fromright-to-left shunting as a means to improve low systemic cardiacoutput. Several of the embodiments described in this disclosure would beprovide improved performance compared to right-to-left shunts currentlyavailable to that population of patients.

Another geometrical constraint is the frequent presence or need to placetransvenous endocardial electrical pacing or defibrillation leads in orthrough the RA of heart failure patients. In the 38-patient feasibilitystudy conducted with the V-Wave Nitzan-type shunt, 74% of patients hadalready been implanted with cardiac rhythm management devices prior tointeratrial shunting. Most of these patients had 2 or 3 such electricalleads placed. Leads most often enter the RA from the superior vena cava(SVC). Right atrial pacing leads usually loop up and terminateanterio-laterally in the RA appendage, but in some circumstances, theyare attached to a muscular portion of the interatrial septum. RV pacingand defibrillation leads usually course along the lateral wall of theRA, then cross the tricuspid valve, and terminate in theinterventricular septum, RV apex, or pulmonary outflow tract. LV leadsenter the coronary sinus, which is just below and anterior to the FO.Occasionally, leads must be placed from unusual sites of origin and mayenter the RA from the inferior vena cava (“IVC”). Leads are usually leftwith enough slack so that they do not put tension on their terminal endswhen the heart moves or changes position. Much of this slack results ina web of excess lead body material that is often concentrated in the RA.

The observations of septal bowing, the range of chamber dimensionsobserved and the consequences of multiple transvenous endocardial leadplacement have important implications for interatrial shunt devicedesign. If a shunt protrudes into the LA chamber, it preferably isplaced so that it generally projects orthogonally with respect to the FOas shown in FIG. 8A. Orthogonal placement is expected to minimizeimpingement on other adjacent or nearby critical cardiac structures,such as the aortic root, the mitral valve annulus, the roof and theposterior wall of the LA, and the pulmonary veins. Alternatively, if notplaced substantially orthogonally, as shown in FIG. 9A, the shuntgeometry should be selected to prevent the shunt from interacting withthese structures. Proper accounting for such design considerations willprevent erosion of the shunt into critical cardiac structures, andprevent blockage of flow through the shunt by luminal impingement byadjacent cardiac structures. Ideally, the shunt should also occupyminimal space within the LA and only minimally disturb its normal flowpattern. The LA fills from the pulmonary veins during ventricularsystole and drains into the left ventricle when the mitral valve opensduring diastole. Blood coming from the right superior pulmonary veinstends to course along and hug the interatrial septum preventing stasisnear the FO.

In a preferred embodiment of shunt 10, the volume of blood displaced bythe portion of the shunt protruding into the LA, i.e., the volume ofblood in the portion of the shunt lumen protruding into the LA, shouldbe less than or equal to 5% of the LA diastolic volume expected in thepatient population. This is typically 2.0 ml or less in adult patientswith heart failure. Moreover, the shunt should not protrude into the LAby more than 15 mm, or more typically 3 to 10 mm. These dimensionalconsiderations may also be accomplished in conjunction with other shuntfeatures that facilitate a substantially orthogonal orientation, such asan LA entry funnel.

Similar considerations exist for the RA side of the FO. The shunt shouldoccupy a minimal volume and have only a small effect on normal flowpatterns. In a preferred embodiment, the same occupying volume andprotrusion distance considerations, apply to the RA side of the shunt,that is, the device and its lumen should occupy less than or equal to 5%of the RA diastolic volume, e.g., 2.0 ml or less in adult patients withheart failure, and protrude into the RA by no more than, for example, 15mm, or more typically 3 to 10 mm. These dimensional considerations canalso be accomplished in conjunction with other shunt features thatfacilitate a substantially orthogonal orientation, such as RA exitfunnel. These same criteria apply when the shunt is used in anapplication where RA to LA shunting is desirable, e.g., pulmonaryarterial hypertension (PAH). The shunt should protrude in the RA theleast amount necessary so that it does not foul pacing leads or abradetheir electrical insulation.

As described earlier, the propensity for venous thromboembolism (“VTE”)to cross in the retrograde direction through a shunt is expected to be afunction of not only the amount and duration of retrograde shunt flowfrom the RA to the LA, but also a result of the flow patterns in the RA.The path of flow in the adult RA is complex because blood enters thechamber from multiple sources which include the inferior vena cava(IVC), the superior vena cava (SVC), the coronary sinus and from the LAthrough the shunt. These flow paths include directional changes andasymmetries whose topology has been assessed by color flow Dopplerimaging and more recently from magnetic resonance velocity mapping.

Since the overwhelming majority of VTE in adult patients originate fromthe lower extremities and pelvic veins, the path traveled by paradoxicalemboli are most likely similar to the flow vectors for blood coming fromthe IVC. Flow from the inferior vena cava courses along the posteriorwall of the RA chamber before looping around the roof, where it isdirected toward the tricuspid valve by coursing along the interatrialseptum. The rest of the cavity generally contains pooled blood. Thus,blood entering the RA from the IVC forms a clockwise vortex descendingalong the RA side of the interatrial septum in most patients with normalanatomy. Advantageously, this flow pattern of blood downwards from theroof of the RA and along the interatrial septum reduces the risk ofblood pooling in the vicinity of neck region 16 of the inventive shunt10, thus reducing the risk of local thrombus formation due to bloodstasis. Further, these flow pathway observations suggest that a thrombusoriginating from inferior vena cava will a have a trajectory that passesvery close to the RA orifice of a naturally occurring secundum typeatrial septal defect or an orifice-plate mesh type shunt. Because inthis case thrombus is essentially presented by the flow path within theRA to the orifice, even a small reversal of shunt flow could embolizethe thrombus across the orifice into the LA.

In accordance with another aspect of the present invention, a preferredembodiment of an inventive shunt includes an exit port (end region 14)that extends a distance into the RA, e.g., 3 to 15 mm, or more typically5 to 10 mm, sufficient to place the orifice of the exit port out of thenaturally occurring flow paths in the RA. In particular, the exit portprojects partially or completely through the stream of blood originatingfrom the IVC that loops down across the interatrial septum. Such a shuntgeometry thus will be expected to have a lower risk of paradoxicalembolization compared with an orifice-plate mesh type shunt where theexit port is directed at the passing looped IVC flow stream.

Referring now to FIGS. 10 and 11, additional alternative embodiments aredescribed, where a conduit is registered with respect to the fossaovalis of the interatrial septum by an external, unencapsulated baremetal anchor similar to anchor 12 of the embodiment of FIGS. 1A-1C.Specifically, shunt 80 of FIG. 10 includes anchor 81, which may beemployed to register conduit 82 within the interatrial septum. Conduit82 may include a separate encapsulated tubular frame or may comprise atube of solid material, and may include a variety of geometries toachieve specific characteristics as previously described. Anchor 81 andconduit 82 may be physically affixed to each other prior to insertion inthe body by mechanical interference, welding, adhesives, or otherwell-known means, and preferably includes a skirt that prevents bypassflow between anchor 81 and conduit 82. Alternatively, anchor 81 may bedelivered across the septum deployed, and then conduit 82 may beinserted through and deployed within anchor 81 and held in place bymechanical interference or expansion with a balloon. The advantages ofsuch a two-part design are two-fold. First, pannus will grow thick onlyon the outside surface of anchor 81 because the LA and RA ends ofconduit 82 are offset from, and thus do not contact, adjacent cardiacstructures. Second, the design creates a longest straight channel forhigh velocity flow, but limits the ability of paradoxical emboli totransit conduit 82 during a transient pressure gradient reversal. Thedimensional aspects noted above with respect to the description of shunt10 of FIG. 1C above may be applied to shunt 80.

FIG. 11 illustrates another preferred embodiment with benefits similarto that of the shunt of FIG. 10. More specifically, shunt 90 may includeanchor 91 as described above with the respect to frame 12 of theembodiment of FIGS. 1A-1C. Conduit 92 may include flared end regions asdescribed above, e.g., to form an hourglass shape in the deployed state.One of ordinary skill in the art will appreciate that the specific shapeof the flared end regions may be conical, parabolic, or horned shaped,and may be present at either or both ends of the shunt device dependingon the desired hydraulic properties. The dimensional aspects noted abovewith respect to the description of shunt 10 of FIG. 1C above may beapplied to shunt 90.

The shunt types depicted in FIG. 10 and FIG. 11, or shunts with similarcharacteristics that would be apparent to one of ordinary skill in theart, may be particularly applicable to the clinical situation where toolarge an aperture defect has been created in the FO and whereinteratrial shunting to treat heart failure is required. Consider thecase of a patient with severe mitral regurgitation and poor leftventricular function, where it would be clinically desirable to firstperform a repair procedure on the mitral valve, e.g. MitraClip® ofmitral annuloplasty by the percutaneous transseptal approach, followedby interatrial shunt placement. These mitral valve procedures currentlyuse a 23Fr I.D. (˜8 mm O.D) guiding catheter to cross the FO. Aftermitral repair, an anchor with an outer minimal diameter matching thelarger aperture defect caused by the prior procedure may be implanted,wherein the conduit as a smaller diameter desirable for shunting (e.g.5.0 to 6.5 mm). Likewise, such shunts advantageously may be used where,during the transseptal procedure, the fossa ovalis has been torn, thuscreating a larger aperture defect than required for various shuntembodiments described with respect to FIGS. 1 to 5. Again, a shunt ofthe kind described with respect to FIG. 10 or 11 could be used toaddress such a situation.

FIGS. 12-15 show further alternative shunt embodiments 95, 100, 110 and120, respectively that use different shunt geometries in combinationwith anchors and anchoring tabs. The conduits of these shunts may becylindrical, conical or have other lumen geometries as previouslydescribed herein. More specifically, in FIG. 12 anchor 95 suitable foruse in an inventive shunt includes flared region 96 configured fordeployment in the left atrium and substantially cylindrical region 97that extends through the atrial septum and into the right atrium.Flexible struts 98 bend distally, i.e., towards the septum when theanchor is released from its delivery sheath, and preferably includeU-shaped inverted ends that contact, but do not penetrate, the rightatrial wall in the fully deployed position, as depicted in FIG. 12.Preferably, anchor 95, other than flexible struts 98 includes a conduitformed by encapsulating the anchor with polymeric material that preventstissue ingrowth from obstructing the lumen of cylindrical region 97, andmay be made of a biocompatible shape memory alloy, as described forpreceding embodiments.

Shunt 100 of FIG. 13 may include a plurality of collapsible tab-likeretention elements 101 disposed on the RA region of a cylindrical shunt.Retention elements 101 are designed to engage the FO to preventmigration/embolization of shunt 100 into the LA or beyond. With amuch-thickened FO, retention elements 101 may become buried within theFO wall itself. In addition, shunt 100 may include conical anchor 102extending at an angle into the LA from the LA side 103 of shunt 100,similar in construction to flared end region 18 of frame 12 of theembodiment of FIGS. 1A-1C. The advantage of this configuration is thatit may be deployed in an FO that has any wall thickness (typically up to10 mm). The other dimensional aspects noted above with respect to thedescription of shunt 10 of FIG. 1C above may be applied to shunt 100.

In FIG. 14, shunt 110 is similar in construction to shunt 100 andincludes retention elements 111 on the RA side, but omits conical anchor102 on the LA side. Instead, shunt 110 may include plurality ofcollapsible tabs 112 on LA side 113 of the shunt designed to offsetcylindrical shunt 110 from the FO or other cardiac structures. Anadvantage of this configuration is that there is less structureoccupying the free space in the LA. The other dimensional aspects ofshunt 10 of FIG. 1C above may be applied to shunt 110.

In FIG. 15, shunt 120 comprises an encapsulated expanded LA side 121,and a simple cylinder on RA side 122 that includes a plurality ofretention elements 123. An advantage of this configuration is that shunt120 may be constructed from a singular tubular frame. The otherdimensional aspects of shunt 10 of FIG. 1C above may be applied to shunt120.

Referring now to FIGS. 16A and 16B, anchor 130 of an alternativeembodiment of a shunt constructed in accordance with the principles ofthe present invention is described. Anchor 100 is similar to anchor 12of the embodiment of FIGS. 1A-1C, but further includes a plurality offlexible arms 131 attached to the circumferential strut nearest the exitport in the right atrium. Flexible arms 131 self-expand when the shuntis deployed to form a meshwork or filter that partially obstructs theexit port of the shunt. In particular, upon deployment, flexible arms131 unfold to extend across the lumen in the vicinity of the lumen ofthe RA exit port, ideally near the location of its widest opening, toform a filter that prevents larger paradoxical emboli from passing intothe left atrium. Flexible arms 131 permit blood to pass in eitherdirection with minimal resistance while excluding the passage ofparadoxical emboli that are generally larger than the mesh size, e.g.,venous thromboemboli above a certain size, which may be on a paradoxicaltrajectory. In this case, the size of the emboli excluded is determinedby the geometry of mesh. Prior to deployment, these arms may also serveas locations of attachment of the shunt to its delivery system. While inthe embodiment depicted in FIGS. 16A and 16B, flexible arms 131 comprisestruts that fold across the exit port of anchor 130 upon deployment, inalternative embodiments, flexible arms 130 may take any of a number ofconfigurations, including a plurality or multiplicity of bars or archesthat fold across the exit port to create a filter. In an alternativeembodiment, as already described, larger paradoxical emboli could beexcluded by having a plurality of passageways or lumina through theshunt device.

FIG. 17 is a graph depicting the effects of orifice size on the flowcharacteristics, e.g., bench testing quantified flow vs. pressurerelationships, of two types of V-Wave Nitzan-type shunts as described inthe above-incorporated application. Measurements were made in saline at37 degrees Celsius, under constant pressure gradient conditions over theexpected range of left-to-right pressure gradients. Flow was measuredfor the V-Wave 5.1 mm inner diameter orifice Nitzan-typehourglass-shaped valveless shunt and for a 6-mm inner diameter orificevalveless version of the shunt built upon the same nitinol frame. Asdepicted in FIG. 17, the 6-mm shunt has about 35% more flow than the 5mm valved shunt. Also shown in FIG. 17, is the simulated flow forventuri tubes with orifice inner diameters of 5.1 and 6 mm withdischarge coefficients of 0.97 and 0.96 respectively. These data suggestthat the performance of the valveless hourglass shunts is closelyapproximated by a classical venturi. Simulations of a conical convergentnozzle (not shown) with a convergence angle of 37 and 36 degrees and adischarge coefficient of 0.92 for the 5.1 and 6 mm orifice innerdiameters, respectively, showed similar predictive accuracy with actualshunts.

Referring again to FIG. 6, that figure depicts theoretical flows for a5.1 mm and 6.0 mm venturi tube (discharge coefficient 0.97 and 0.96,respectively), as described above, along with flows through 6.4 mm and7.5 mm orifice plates (discharge coefficient 0.61), respectively. Asshown in FIG. 6, an orifice plate device requires an inner diameter of7.5 mm to have flow characteristics similar to a 6 mm venturi tube.Similarly, an orifice plate device requires an inner diameter of about6.4 mm to have flow characteristics similar to f a 5.1 mm venturi tube.These measured data and simulations show that the valveless lumen of thehourglass-shaped V-Wave Nitzan-type shunt is more efficient atsupporting bulk flow over the expected physiological range of pressuregradients than an orifice-plate shunt.

In particular, an hourglass-shaped shunt permits a smaller orifice thanan orifice-plate shunt with similar bulk flow capacity (7-8 mm indiameter). The smaller orifice, in turn, prevents proportionally largerthrombi from passing retrograde through the shunt and into the systemiccirculation. Since ischemic damage from the lodging of embolus islimited to the watershed organ territory supplied by the occludedvessel, larger emboli tend to cause more damage and have more associateddangerous consequences, especially when the occluding vessel suppliesthe brain. Thus, with a smaller orifice size, paradoxical embolicstrokes, if they occur, are likely to be smaller than with anorifice-plate mesh type shunt. Accordingly, in a preferred embodiment, ashunt having a discharge coefficient of 0.70 or greater will, by virtueof its smaller diameter or area orifice, have less tendency forparadoxical embolization than an orifice-plate mesh shunt with similarflow characteristics.

Clinical studies conducted using a orifice-plate mesh shunt offered byCorvia Medical, Inc., Tewksbury, Mass., indicate that a 8-mm Corviaorifice-plate mesh shunt had a Qp/Qs=1.27±0.20 at 6 months compared to1.06±0.32 just prior to implantation. This ratio was likely higher justafter implantation due to some degree of shunt narrowing as a result ofpannus formation that would be expected by 6 months. By comparison, forthe V-Wave Nitzan-type valved shunt with a 5 mm orifice inner diameter,Qp/Qs derived from echo/Doppler analysis in the aforementioned patientcohort was relatively small at 1.18±0.16 shortly after implant comparedto 1.04±0.22 at baseline (p<0.03). Qp/Qs decreased slightly to 1.12±0.14by 6-12 months (p=0.10), consistent with the observed narrowing of theshunts over this same time period. These data suggest that the V-WaveNitzan-type valved shunt, that was shown to have substantial earlyclinical benefit, was associated with a very small Qp/Qs ratio, and noevidence of worsening right heart failure or pulmonary hypertension. Thedata also suggest that a shunt of similar geometry can be made with alarger inner diameter, e.g., 6.5 mm inner diameter, without exceeding aQp/Qs ratio of 1.5:1.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

While various illustrative embodiments of the invention are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made herein without departing from theinvention.

1. A device for regulating blood volume distribution configured forplacement in an interatrial septum between a patient's left atrium andpatient's right atrium, the device comprising: an anchor having a firstregion, a second region, a neck region joining the first region to thesecond region, the anchor configured to transition from a contracteddelivery state to an expanded deployed state in which the first regionextends into the patient's left atrium, the second region extends intothe patient's right atrium, and the neck region contacts the interatrialseptum; a conduit affixed to the anchor and having a lumen wall defininga lumen, the lumen wall resistant to transmural and translational tissuegrowth, the conduit having a first end that extends from the neck regiona first distance of at least 3 mm into the patient's left atrium and asecond end that extends from the neck region a second distance of atleast 3 mm into the patient's right atrium, thereby preventing pannusformation from narrowing the lumen in the neck region.
 2. The device ofclaim 1, wherein the conduit is configured so that when implanted thesecond end of the conduit is located out of a natural circulation flowpath of blood entering into the patient's right atrium from an inferiorvena cava, thereby reducing a risk of emboli entrained in flow from theinferior vena cava being directed into the second end of the conduit. 3.The device of claim 2, wherein the second end is configured to extendinto the right atrium a distance of at least 5 mm when implanted.
 4. Thedevice of claim 1, wherein the second end is configured so that whenimplanted the neck region engages a fossa ovalis of the patient'sinteratrial septum and the second end protrudes a distance of between 3mm to 15 mm into the patient's right atrium.
 5. The device of claim 1,wherein the lumen has a smallest diameter in the neck region in a rangeof 5 mm to 6.5 mm.
 6. The device of claim 1, wherein at least the firstregion is flared.
 7. The device of claim 1, wherein the conduitcomprises a layer of biocompatible material disposed on the anchor andan exterior surface of the conduit is impermeable to transmural tissuegrowth and resistant to translational tissue growth.
 8. The device ofclaim 1, wherein the anchor has a diameter in the expanded deployedstate larger than a diameter of the conduit, such that when implantedthe anchor fills a larger opening in the interatrial septum than isneeded to accommodate the conduit.
 9. The device of claim 1, wherein alength of the anchor is different than a leneth of the conduit.
 10. Thedevice of claim 1, wherein the anchor, in the expanded deployed state,forms a filter that prevents emboli from entering the second end of theconduit.
 11. (canceled)
 12. A device for regulating blood volumedistribution between a patient's left atrium and right atrium, thedevice comprising: an anchor having, in a deployed state, a first regionconfigured to be disposed in the patient's left atrium, a second regionconfigured to be disposed in a right atrium, and a neck region disposedbetween the first and second regions, the neck region configured toengage a fossa ovalis of an atrial septum; a conduit affixed to theanchor and having a lumen that extends through the first region, thesecond region and the neck region, the conduit configured so that whenimplanted an end of the conduit protrudes into the right atrium adistance sufficient to place the end out of a natural circulation flowpath in the right atrium, thereby reducing a risk that thrombusentrained in the natural circulation flow path will be directed into thelumen.
 13. The device of claim 12, wherein the distance is greater thanor equal to 5 mm.
 14. The device of claim 12, wherein a wall of theconduit is resistant to transmural and translational tissue growth andthe conduit extends into each of the first region and the second regionat least 3 mm beyond a location of contact of the anchor to any cardiacstructure.
 15. The device of claim 12, wherein at least one of the firstregion and the second region is flared.
 16. The device of claim 12,wherein the conduit encapsulates the anchor.
 17. The device of claim 12,wherein the anchor has a diameter in the expanded deployed state largerthan a diameter of the conduit, such that the anchor is configured tofill a larger opening in the interatrial septum than needed toaccomodate the conduit.
 18. The device of claim 12, wherein conduit hasa length different than a length of the anchor.
 19. The device of claim12, wherein the anchor comprises, in the expanded deployed state, afilter that excludes emboli from entering the lumen.
 20. The device ofclaim 12, wherein the anchor comprises a plurality of longitudinalstruts, a subset of the longitudinal struts having eyelets configured toengage a delivery device.
 21. The device of claim 20, wherein a subsetof the longitudinal struts include radiopaque markers.
 22. The device ofclaim 20, wherein the anchor further comprises a plurality ofcircumferential sinusoidal struts interconnecting the longitudinalstruts, and the conduit encapsulates the anchor except for a portiondefining cutouts adjacent to the end of the conduit.